interacts_with DB01367?
P14416 signaling dynamics of dopamine D2-neurotensin 1 receptor heteromers . Biochemical , histochemical and coimmunoprecipitation experiments have indicated the existence of antagonistic dopamine D2 ( D2R ) and neurotensin 1 ( NTS1R ) receptor-receptor interactions in the dorsal and ventral striatum indicating a potential role of these receptor-receptor interactions in Parkinson 's disease and schizophrenia . By means of Bioluminiscence Resonance energy transfer ( BRET(2) ) evidence has for the first time been obtained in the current study for the existence of both D2LR/NTS1R and D2SR/NTS1R heteromers in living HEK293T cells . Through confocal laser microscopy the NTS1R(GFP2) and D2R(YFP) were also shown to be colocated in the plasma membrane of these cells . A bioinformatic analysis suggests the existence of a basic set of three homology protriplets ( TVM , DLL and/or LRA ) in the two participating receptors which may contribute to the formation of the D2R/NTS1R heteromers by participating in guide-clasp interactions in the receptor interface . The CREB reporter gene assay indicated that the neurotensin receptor agonist JMV 449 markedly reduced the potency of the D2R like agonist quinpirole to inhibit the forskolin induced increase of the CREB signal . In contrast , the neurotensin agonist was found to markedly increase the quinpirole potency to activate the MAPK pathway as also studied with luciferase reporter gene assay measuring the degree of SRE activity as well as with P27361 /2 phosphorylation assays . These dynamic changes in D2R signaling produced by the neurotensin receptor agonist may involve antagonistic allosteric receptor-receptor interactions in the D2LR-NTS1R heteromers at the plasma membrane level ( CREB pathway ) and synergistic interactions in PKC activation at the cytoplasmatic level ( MAPK pathway ) . Application of HapMap data to the evaluation of 8 candidate genes for pediatric slow transit constipation . BACKGROUND : Slow transit constipation ( P52823 ) affects up to 3 % of all children and is an increasingly recognized cause of chronic constipation in children . We conducted a pilot study to investigate whether genes encoding neurotransmitters ( P20366 , Q9UHF0 , P01282 , NOS1 ) and receptors ( P25103 , P21452 , P29371 , P10721 ) could be responsible for P52823 . METHODS : One hundred seventeen tag single nucleotide polymorphisms ( SNPs ) , distributed among the candidate genes , were selected from HapMap data and genotyped using Sequenom ( San Diego , CA ) technology in 35 affected families . Evaluation of association was performed by transmission disequilibrium test and multilocus analysis . RESULTS : Five SNPs ( rs3771863 , rs4580655 , rs11722288 , rs4563545 , and rs3782221 ) in the P25103 , P29371 , P10721 , and NOS1 genes were found to be potentially associated with P52823 , although the significance of these results does not withstand correction for multiple testing . CONCLUSIONS : Our data indicate that 5 SNPs in the NOS1 , P25103 , P29371 , and P10721 genes could be involved in P52823 , especially rs3771863 in intron 1 of P25103 , which showed the highest association . Effects of maternal smoking on the placental expression of genes related to angiogenesis and apoptosis during the first trimester . OBJECTIVE : Maternal cigarette smoking is reportedly associated with miscarriage , fetal growth restriction and placental abruption , and is paradoxically associated with a decreased risk of developing preeclampsia . In the present study , we investigated the gene expression levels of villous tissues in early gestation . We compared the expression levels of the genes related to angiogenesis and apoptosis in the villous tissues obtained from smoking and non-smoking pregnant women . MATERIALS AND METHODS : We collected villous tissue samples from 57 women requesting surgical termination due to non-medical reasons at 6-8 weeks of gestation . The maternal cigarette smoking status was evaluated by the level of serum cotinine and patients were divided into active smokers and non-smokers by the serum cotinine level . The placental levels of P15692 , P49763 , P17948 , Q16665 , P04637 , Q07812 and P10415 mRNA were quantified by real time PCR . RESULTS : The gene expression level of P49763 and Q16665 in the active smoker group was significantly higher than that in the non-smoker group . We did not observe any significant differences in the P15692 or P17948 expression between the groups . In active smoker group , the gene expression levels of P04637 and Q07812 were significantly higher than those in the non-smoker group . The ratio of Q07812 / P10415 mRNA in the active smoker group was significantly higher than that in the non-smoker group . CONCLUSIONS : Our findings revealed that smoking might affect the placenta during early pregnancy . Maternal cigarette smoking in early pregnancy may be associated with villus hypoxia , which may influence angiogenesis and apoptosis . Interaction of tacrolimus(FK506) and its metabolites with FKBP and calcineurin . DB00864 (FK506) is a strong immuno-suppressant and shows its activity through inhibiting P60568 mRNA transcription by forming pentameric complex with intracellular receptor ( FK506 binding protein 12 kDa or P62942 ) , Ca2+ , calmodulin , and calcineurin . Here , we report the binding activity to P62942 , the pentameric complex formation and Con-A response inhibiting activities of 7 metabolites . C15-demethylated metabolite(M-3) needed higher quantity to compete in Con-A assay and in pentamer formation assay , although it binds more strongly to P62942 . The result suggests that the ability to form a pentameric complex is not a two step reaction with the first binding to P62942 , but a single step reaction by components for the pentamer formation . Signatures of positive selection in genes associated with human skin pigmentation as revealed from analyses of single nucleotide polymorphisms . Phenotypic variation between human populations in skin pigmentation correlates with latitude at the continental level . A large number of hypotheses involving genetic adaptation have been proposed to explain human variation in skin colour , but only limited genetic evidence for positive selection has been presented . To shed light on the evolutionary genetic history of human variation in skin colour we inspected 118 genes associated with skin pigmentation in the Perlegen dataset , studying single nucleotide polymorphisms ( SNPs ) , and analyzed 55 genes in detail . We identified eight genes that are associated with the melanin pathway ( Q9UMX9 , Q04671 , P17643 , P40126 , P21583 , P00533 , P14416 and Q03181 ) and presented significant differences in genetic variation between Europeans , Africans and Asians . In six of these genes we detected , by means of the EHH test , variability patterns that are compatible with the hypothesis of local positive selection in Europeans ( Q04671 , P17643 and P21583 ) and in Asians ( Q04671 , P40126 , P21583 , P00533 and P14416 ) , whereas signals were scarce in Africans ( P40126 , P00533 and P14416 ) . Furthermore , a statistically significant correlation between genotypic variation in four pigmentation candidate genes and phenotypic variation of skin colour in 51 worldwide human populations was revealed . Overall , our data also suggest that light skin colour is the derived state and is of independent origin in Europeans and Asians , whereas dark skin color seems of unique origin , reflecting the ancestral state in humans . Risk stratification of intermediate-risk acute myeloid leukemia : integrative analysis of a multitude of gene mutation and gene expression markers . Numerous molecular markers have been recently discovered as potential prognostic factors in acute myeloid leukemia ( AML ) . It has become of critical importance to thoroughly evaluate their interrelationships and relative prognostic importance . Gene expression profiling was conducted in a well-characterized cohort of 439 AML patients ( age < 60 years ) to determine expression levels of EVI1 , P19544 , P10415 , P08183 , Q8WXS3 , P36888 , P28906 , P14902 , ERG and Q10571 . A variety of AML-specific mutations were evaluated , that is , P36888 , P06748 , N- DB01367 , K- DB01367 , O75874 , P48735 , and P49715 (DM/SM) ( double/single ) . Univariable survival analysis shows that ( 1 ) patients with P36888 (ITD) mutations have inferior overall survival ( OS ) and event-free survival ( O43281 ) , whereas P49715 (DM) and P06748 mutations indicate favorable OS and O43281 in intermediate-risk AML , and ( 2 ) high transcript levels of Q8WXS3 , P28906 , Q10571 , EVl1 , and ERG predict inferior OS and O43281 . In multivariable survival analysis , P28906 , ERG , and P49715 (DM) remain significant . Using survival tree and regression methodologies , we show that P49715 (DM) , P28906 , and P48735 mutations are capable of separating the intermediate group into 2 AML subgroups with highly distinctive survival characteristics ( OS at 60 months : 51.9 % vs 14.9 % ) . The integrated statistical approach demonstrates that from the multitude of biomarkers a greatly condensed subset can be selected for improved stratification of intermediate-risk AML . Dependence on phosphoinositide 3-kinase and DB01367 -RAF pathways drive the activity of RAF265 , a novel RAF/ P35968 inhibitor , and RAD001 ( DB01590 ) in combination . Activation of phosphatidylinositol-3-kinase ( PI3K ) -AKT and Kirsten rat sarcoma viral oncogene homologue ( P01116 ) can induce cellular immortalization , proliferation , and resistance to anticancer therapeutics such as epidermal growth factor receptor inhibitors or chemotherapy . This study assessed the consequences of inhibiting these two pathways in tumor cells with activation of P01116 , PI3K-AKT , or both . We investigated whether the combination of a novel RAF/vascular endothelial growth factor receptor inhibitor , RAF265 , with a mammalian target of rapamycin ( P42345 ) inhibitor , RAD001 ( everolimus ) , could lead to enhanced antitumoral effects in vitro and in vivo . To address this question , we used cell lines with different status regarding P01116 , P42336 , and P15056 mutations , using immunoblotting to evaluate the inhibitors , and MTT and clonogenic assays for effects on cell viability and proliferation . Subcutaneous xenografts were used to assess the activity of the combination in vivo . RAD001 inhibited P42345 downstream signaling in all cell lines , whereas RAF265 inhibited RAF downstream signaling only in P15056 mutant cells . In vitro , addition of RAF265 to RAD001 led to decreased AKT , S6 , and P06730 binding protein 1 phosphorylation in HCT116 cells . In vitro and in vivo , RAD001 addition enhanced the antitumoral effect of RAF265 in HCT116 and H460 cells ( both P01116 mut , P42336 mut ) ; in contrast , the combination of RAF265 and RAD001 yielded no additional activity in A549 and MDAMB231 cells . The combination of RAF and P42345 inhibitors is effective for enhancing antitumoral effects in cells with deregulation of both DB01367 -RAF and PI3K , possibly through the cross-inhibition of 4E binding protein 1 and S6 protein . Fibroblast growth factor-2 in hyperplastic pituitaries of D2R knockout female mice . P14416 ( D2R ) knockout ( KO ) female mice develop chronic hyperprolactinemia and pituitary hyperplasia . Our objective was to study the expression of the mitogen fibroblast growth factor ( P09038 ) and its receptor , P11362 , comparatively in pituitaries from KO and wild-type ( WT ) female mice . We also evaluated P09038 subcellular localization and P09038 effects on pituitary function . P09038 -induced prolactin release showed a similar response pattern in both genotypes , even though basal and P09038 -stimulated release was higher in KO . P09038 stimulated pituitary cellular proliferation ( MTS assay and [(3)H]thymidine incorporation ) , with no differences between genotypes . P09038 concentration ( measured by ELISA ) in whole pituitaries or cultured cells was lower in KO ( P < 0.00001 and 0.00014 ) . Immunofluorescence histochemistry showed less P09038 in pituitaries from KO females and revealed a distinct P09038 localization pattern between genotypes , being predominantly nuclear in KO and cytosolic in WT pituitaries . Finally , P09038 could not be detected in the conditioned media from pituitary cultures of both genotypes . P11362 levels ( Western blot and immunohistochemistry ) were higher in pituitaries of KO . Basal concentration of phosphorylated ERKs was lower in KO cells ( P = 0.018 ) . However , when stimulated with P09038 , a significantly higher increment of P29323 phosphorylation was evidenced in KO cells ( P < or = 0.02 ) . We conclude that disruption of the D2R caused an overall decrease in pituitary P09038 levels , with an increased distribution in the nucleus , and increased P11362 levels . These results are important in the search for reliable prognostic indicators for patients with pituitary dopamine-resistant prolactinomas , which will make tumor-specific therapy possible . Efficacy and safety of repeated dosing of netupitant , a neurokinin-1 receptor antagonist , in treating overactive bladder . AIM : NK-1 receptors in sensory nerves , the spinal cord and bladder smooth muscle participate in complex sensory mechanisms that regulate bladder activity . This study was designed to assess the efficacy and safety of a new P25103 antagonist , netupitant , in patients with OAB . METHODS : This was a phase II , multicenter , double-blind study in which adults with OAB symptoms > 6 months were randomized to receive 1 of 3 doses of netupitant ( 50 , 100 , 200 mg ) or placebo once daily for 8 weeks . The primary efficacy endpoint was percentage change from baseline in average number of daily micturitions at week 8 . Urinary incontinence , urge urinary incontinence ( UUI ) , and urgency episodes were also assessed . RESULTS : The primary efficacy endpoint was similar in the treatment groups ( -13.85 for placebo to -16.17 in the netupitant 200 mg group ) with no statistically significant differences between netupitant and placebo . The same was true for most secondary endpoints although a significant difference for improvement in UUI episodes and a trend for the greatest decrease in urgency episodes were seen in the netupitant 100 mg group . DB09048 was well tolerated with most treatment emergent adverse events ( AEs ) being mild . While the overall incidence of AEs increased with netupitant dose , there was no evidence for this dose dependency based on relationship to treatment , intensity , or time to onset . CONCLUSIONS : The study failed to demonstrate superiority of netupitant versus placebo in decreasing OAB symptoms , despite a trend favoring netupitant 100 mg . There were no safety concerns with daily administration of netupitant over 8 weeks . Phorbol ester-mediated inhibition of growth and regulation of proto-oncogene expression in the human T cell leukemia line JURKAT . The expression and function of several proto-oncogenes were examined in a human acute T cell leukemia line , JURKAT , during phorbol ester-induced terminal differentiation . Treating JURKAT cells with the phorbol ester tetradecanoyl phorbol acetate ( TPA ) inhibited their proliferation and induced expression of the gene for the interleukin 2 receptor alpha chain ( IL2R-alpha ) , consistent with previous reports . In unstimulated proliferating JURKAT cells , high levels of C-MYC , N- DB01367 , and P10415 mRNAs were found that diminished rapidly following TPA-induced cessation of growth . In contrast , accumulation of mRNAs for the C- P01100 , C- P05412 , and P18146 genes increased markedly in TPA-treated cells and preceded the induction of IL2R-alpha mRNA . Expression of C- P10242 , C-RAF-1 , C- P06239 , C- P06241 , and C- P09769 proto-oncogenes was relatively unchanged . To explore directly the function of two of these protooncogenes in regulating the growth of JURKAT T cells , we stably transferred C-MYC and P10415 expression plasmids into these cells . Despite sustained expression of C-MYC , P10415 , or the combination of these protooncogenes , TPA continued to inhibit JURKAT cell growth and to induce IL2R expression . Thus , although C-MYC and P10415 proto-oncogene expression correlated with proliferation in TPA-treated JURKAT cells , continuous over-expression of even the combination of these oncogenes was insufficient for abrogating the effects of TPA in these leukemic T cells . Because human lymphoid malignancies frequently contain chromosomal translocations that deregulate the expression of C-MYC and P10415 , our findings could have relevance for attempts to induce terminal differentiation of leukemic cells by in vitro exposure of patients ' bone marrow cells to phorbol esters . Unbiased screen for interactors of leucine-rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease . Mutations in leucine-rich repeat kinase 2 ( Q5S007 ) cause inherited Parkinson disease ( PD ) , and common variants around Q5S007 are a risk factor for sporadic PD . Using protein-protein interaction arrays , we identified P10415 -associated athanogene 5 , Rab7L1 ( P51149 , member DB01367 oncogene family-like 1 ) , and O14976 as binding partners of Q5S007 . The latter two genes are candidate genes for risk for sporadic PD identified by genome-wide association studies . These proteins form a complex that promotes clearance of Golgi-derived vesicles through the autophagy-lysosome system both in vitro and in vivo . We propose that three different genes for PD have a common biological function . More generally , data integration from multiple unbiased screens can provide insight into human disease mechanisms . Aberrant microRNA expression likely controls DB01367 oncogene activation during malignant transformation of human prostate epithelial and stem cells by arsenic . Inorganic arsenic ( iAs ) , a human carcinogen , potentially targets the prostate . iAs malignantly transforms the RWPE-1 human prostate epithelial line to CAsE-PE cells , and a derivative normal stem cell ( SC ) line , WPE-stem , to As-Cancer SC ( As-CSC ) line . MicroRNAs ( miRNA ) are noncoding but exert negative control on expression by degradation or translational repression of target mRNAs . Aberrant miRNA expression is important in carcinogenesis . A miRNA array of CAsE-PE and As-CSC revealed common altered expression in both for pathways concerning oncogenesis , miRNA biogenesis , cell signaling , proliferation , and tumor metastasis and invasion . The P01116 oncogene is overexpressed in CAsE-PE cells but not by mutation or promoter hypomethylation , and is intensely overexpressed in As-CSC cells . In both transformants , decreased miRNAs targeting P01116 and DB01367 superfamily members occurred . Reduced miR-134 , miR-373 , miR-155 , miR-138 , miR-205 , miR-181d , miR-181c , and let-7 in CAsE-PE cells correlated with increased target DB01367 oncogenes , RAN , P51159 , Q9UL26 mRNAs , and P01116 protein . Reduced miR-143 , miR-34c-5p , and miR-205 in As-CSC correlated with increased target RAN mRNA , and P01116 , P01111 , and P10301 proteins . The DB01367 / P29323 and PI3K/ P60484 /AKT pathways control cell survival , differentiation , and proliferation , and when dysregulated promote a cancer phenotype . iAs transformation increased expression of activated P29323 kinase in both transformants and altered components of the PI3K/ P60484 /AKT pathway including decreased P60484 and increases in P10415 , BCL-XL , and P15692 in the absence of AKT activation . Thus , dysregulated miRNA expression may be linked to DB01367 activation in both transformants . P01133 -like ligands mediate progesterone 's anti-apoptotic action on macaque granulosa cells . A local autocrine/paracrine role for progesterone is an absolute requirement for corpus luteum formation in primates . Despite this , the mechanism(s) remain obscure , although existing data suggest an anti-apoptotic action to be central . There are a limited number of progestin-regulated gene targets identified in the luteinizing primate follicle , suggesting that a small number of important genes may mediate progesterone action . Possible gene targets could be the epidermal growth factor ( P01133 ) family members amphiregulin ( P15514 ) and epiregulin ( O14944 ) . Using macaques undergoing controlled ovarian stimulation cycles , we show that the phosphorylation of P01133 receptor ( P00533 ) , P29323 1/2 , and AKT increases 6 h after an ovulatory human chorionic gonadotropin ( hCG ) stimulus and remains activate through 24 h . Immunoreactive O14944 and P15514 ligands in the follicular fluid both increased in a time frame commensurate with P00533 phosphorylation . The mRNA expression of P15514 and O14944 in nonluteinized granulosa cells ( NLGC ) was induced in culture with hCG , an effect blocked by progesterone receptor ( P06401 ) antagonists . Overexpression of P06401 B in NLGC and treatment with a nonmetabolizable progestin did not increase either gene , indicating both progesterone and luteinizing hormone/CG are necessary . Addition of P01133 and P01133 -like ligands did not promote steroidogenesis in vitro by granulosa cells in the presence of gonadotropin , but were able to partially reverse DB00834 -induced cell death . These data suggest that progesterone promotes the expression of P15514 and O14944 , which in turn maintain viability of luteinizing granulosa cells , representing one possible mechanism whereby progesterone promotes corpus luteum formation in the primate . P42345 inhibitor RAD001 ( DB01590 ) enhances the effects of imatinib in chronic myeloid leukemia by raising the nuclear expression of c- P00519 protein . Constitutive tyrosine kinase ( TK ) activity of Q92817 P11274 - P00519 fusion protein of chronic myeloid leukemia ( CML ) usurps physiological functions of normal p145 c- P00519 protein . Accordingly , its inhibition by imatinib mesylate ( IM ) lets p145 c- P00519 translocate into the nuclear compartment , which drives cell growth arrest and apoptotic death . Here we show that IM and the mammalian target of rapamycin ( P42345 ) inhibitor RAD001 ( DB01590 ) have additive effects on P11274 - P00519 -expressing cells . Those effects are at least partly conditional upon the enhanced nuclear accumulation of p145 c- P00519 through events encompassing post-translational modifications of p145 c- P00519 ( DB00156 (735) phosphorylation ) precluding its nuclear export and of 14-3-3 sigma ( DB00133 (186) phosphorylation by c-Jun N-terminal kinase [ JNK ] ) promoting p145 c- P00519 nuclear re-import . Steady-state kinetic and inhibition studies of the mammalian target of rapamycin ( P42345 ) kinase domain and P42345 complexes . The mammalian target of rapamycin ( P42345 ) is a DB00133 / DB00156 protein kinase and a major controller of cell growth . In cells , P42345 forms two distinct multiprotein complexes , mTORC1 and mTORC2 . The mTORC1 complex can phosphorylate 4EBP1 and P23443 , two key regulators of translation initiation , whereas mTORC2 phosphorylates P31749 , an event required for P31749 activation . Here , we expressed and purified human mTORC1 and mTORC2 from P29320 -293 cells using FLAG-M2 affinity chromatography . Western blotting analysis using phospho-specific antibodies indicated that recombinant mTORC1 and mTORC2 exhibit distinct substrate preferences in vitro , consistent with their roles in cells . To improve our understanding of the enzymatic properties of P42345 alone and P42345 in its complex form , steady-state kinetic profiles of truncated P42345 containing the kinase domain ( residues 1360-2549 ) and mTORC1 were determined . The results revealed that mTORC1 is catalytically less active than truncated P42345 , as evidenced by 4.7- and 3.1-fold decreases in catalytic efficiency , k(cat)/K(m) , for DB00171 and 4EBP1 , respectively . We also found that truncated P42345 undergoes autophosphorylation through an intramolecular mechanism . Mass spectrometric analysis identified two novel P42345 autophosphorylation sites , Ser2454 and either Thr2473 or Thr2474 , in addition to the previously reported Ser2481 site . Truncated P42345 and mTORC1 were completely inhibited by DB00171 competitive inhibitors PI103 and BEZ235 and partially inhibited by rapamycin/ P62942 in a noncompetitive fashion toward DB00171 . All inhibitors tested exhibited similar inhibitory potencies between mTORC1 and truncated P42345 containing the kinase domain . Our studies presented here provide the first detailed kinetic studies of a recombinant P42345 complex . Effective motion-sensitizing magnetization preparation for black blood magnetic resonance imaging of the heart . PURPOSE : To investigate the effectiveness of flow signal suppression of a motion-sensitizing magnetization preparation ( MSPREP ) sequence and to optimize a 2D MSPREP steady-state free precession ( SSFP ) sequence for black blood imaging of the heart . MATERIALS AND METHODS : Using a flow phantom , the effect of varying field of speed ( P01100 ) , b-value , voxel size , and flow pattern on the flow suppression was investigated . In seven healthy volunteers , black blood images of the heart were obtained at 1.5T with MSPREP-SSFP and double inversion recovery fast spin echo ( P30518 -FSE ) techniques . Myocardium and blood signal-to-noise ratio ( SNR ) and myocardium-to-blood contrast-to-noise ratio ( P21554 ) were measured . The optimal P01100 that maximized the P21554 for MSPREP-SSFP was determined . RESULTS : Phantom data demonstrated that the flow suppression was induced primarily by the velocity encoding effect . In humans , P01100 =10-20 cm/s was found to maximize the P21554 for short-axis ( SA ) and four-chamber ( 4C ) views . Compared to P30518 -FSE , MSPREP-SSFP provided similar blood SNR efficiency in the SA basal and mid-views and significantly lower blood SNR efficiency in the SA apical ( P=0.02 ) and 4C ( P=0.01 ) views , indicating similar or better blood suppression . CONCLUSION : Velocity encoding is the primary flow suppression mechanism of the MSPREP sequence and 2D MSPREP-SSFP black blood imaging of the heart is feasible in healthy subjects . Transformed 3T3 cells have reduced levels and altered subcellular distribution of the major PKC substrate protein P29966 . The P29966 ( myristylated alanine-rich C-kinase substrate ) protein is an abundant calmodulin-binding protein that is a major and specific endogenous substrate of protein kinase C ( PKC ) . Stimulation of cells with phorbol esters or other activators of PKC has been shown previously to result in rapid phosphorylation of P29966 proteins and redistribution of these myristylated C-kinase substrates from membrane to cytosol . Here we show that NIH3T3 murine fibroblasts transformed by P38936 -HA-C- DB01367 or pp60-V- P12931 oncoproteins have markedly reduced levels of p68- P29966 and that most of the remaining P29966 protein is found in the cytosol . 3T3 cells containing a nontransforming oncoprotein Q9Y3Q3 - P10415 , in contrast , exhibited normal levels and distribution of p68- P29966 . When taken together with recent evidence that P29966 proteins are involved in regulating organization of the membrane cytoskeleton , our findings suggest that oncoprotein-mediated alterations in P29966 protein levels and subcellular distribution may contribute to the development or maintenance of the transformed phenotype . Repression of P10415 by the tumor suppressor activity of the lysyl oxidase propeptide inhibits transformed phenotype of lung and pancreatic cancer cells . The gene encoding lysyl oxidase ( P28300 ) was identified as the ras recision gene ( rrg ) , with the ability to revert Ras-mediated transformation of NIH 3T3 fibroblasts . Mutations in DB01367 genes have been found in approximately 25 % of lung cancers and in 85 % of pancreatic cancers . In microarray analysis , these cancers were found to display reduced P28300 gene expression . Thus , the ability of the P28300 gene to repress the transformed phenotype of these cancer cells was tested . P28300 is synthesized as a 50-kDa secreted precursor Pro- P28300 that is processed to the 32-kDa active enzyme ( P28300 ) and to an 18-kDa propeptide ( P28300 -PP ) . Recently , we mapped the rrg activity of Pro- P28300 to the P28300 -PP in Ras-transformed NIH 3T3 cells . Ectopic Pro- P28300 and P28300 -PP expression in H1299 lung cancer cells inhibited growth in soft agar and invasive colony formation in Matrigel and reduced activation of extracellular signal-regulated kinase ( P29323 ) and Akt , with P28300 -PP showing substantially higher activity . Similarly , P28300 -PP expression in PANC-1 pancreatic cancer cells effectively reduced P29323 and Akt activity and inhibited growth in soft agar and ability of these cells to migrate . Nuclear Factor-kappaB ( NF-kappaB ) and its target gene P10415 , which are overexpressed in 70 % to 75 % of pancreatic cancers , have recently been implicated in invasive phenotype . P28300 -PP substantially reduced NF-kappaB and Bcl-2 levels . Reintroduction of Bcl-2 into PANC-1 or H1299 cells expressing P28300 -PP restored the transformed phenotype , suggesting that Bcl-2 is an essential target . Thus , P28300 -PP potently inhibits invasive phenotype of lung and pancreatic cancer cells , suggesting potential therapeutic applications in treatment of these cancers . Gene network profiling before and after transplantation in alcoholic cirrhosis liver transplant recipients . The main objective of this study was to define a gene network profile network in liver transplant recipients with alcoholic cirrhosis before and after liver transplantation . Genes were selected from data obtained in a previous study of liver transplant recipients with alcoholic cirrhosis . Selected up-regulated genes were further validated by quantitative real-time polymerase chain reaction in different groups of liver transplant recipients with alcoholic cirrhosis ( n=5 ) . Selected genes up-regulated before transplantation were : Q07011 ( tumor necrosis factor [ P01375 ] receptor superfamily , member 9 ) ; P14784 ( interleukin-2 receptor beta ) ; Q92843 ( P10415 -like 2 ) ; Q96PH1 ( NADPH ) oxidase , EF-hand calcium binding domain 5 ) ; P50542 ( peroxisomal biogenesis factor 5 ) ; P37231 ( peroxisome proliferator-activated receptor gamma ) ; Q96Q05 ( O14920 binding protein ) ; Q9NYR9 ( NFKappaBeta inhibitor interacting Ras-like 2 ) ; P05112 ( interleukin-4 ) ; IL-4R ( interleukin 4 receptor ) ; P07327 ( alcohol dehydrogenase 1A , class 1 ) ; O75891 ( aldehyde dehydrogenase 1 family , member Q9NUQ9 ) ; P05164 ( myeloperoxidase ) ; P01160 ( natriuretic peptide precursor A ) ; Q16548 ( P10415 -related protein A1 ) ; P24522 ( growth arrest and DNA-damage-inducible alpha ) ; P55061 ( P55061 ) ; P42336 ( phosphoinositide-3-kinase , catalytic , alpha polypeptide ) ; P38484 ( interferon gamma receptor 2 ) ; O60674 ( Janus Kinase 2 ) ; FAS ( Fas , P01375 receptor superfamily , member 6 ) ; Q92844 ( TRAF family member-associated NFKB activator ) ; O95551 ( O95551 ) ; and P08758 ( annexin A5 ) . P01236 activates mitogen-activated protein kinase signaling and corticotropin releasing hormone transcription in rat hypothalamic neurons . P01236 ( PRL ) modulates maternal behavior and mediates hypothalamic pituitary adrenal axis inhibition during lactation via PRL receptors in the brain . To identify mechanisms mediating these effects , we examined the effects of PRL on signaling and P06850 transcription in hypothalamic neurons in vivo and in vitro . Western blot of hypothalamic proteins from rats receiving intracerebroventricular PRL injection revealed increases in phosphorylation of the MAPK and P29323 . Double-staining immunohistochemistry demonstrated phosphorylated P29323 localization in parvocellular P06850 neurons as well as magnocellular vasopressin and oxytocin neurons of the hypothalamic paraventricular ( PVN ) and supraoptic nuclei . PRL also induced P29323 phosphorylation in vitro in the hypothalamic cell line , 4B , which expresses PRL receptors , and in primary hypothalamic neuronal cultures . Using reporter gene assays in 4B cells , or quantitative RT-PCR for primary transcript in hypothalamic cell cultures , PRL potentiated forskolin-stimulated P06850 transcription through activation of the P29323 /MAPK pathway . The effect of PRL in hypothalamic cell cultures was unaffected by tetrodotoxin , suggesting a direct effect on P06850 neurons . The data show that PRL activates the P29323 /MAPK pathway and facilitates P06850 transcription in P06850 neurons , suggesting that the inhibitory effect of PRL on hypothalamo-pituitary-adrenal axis activity reported in vivo is indirect and probably mediated through modulation of afferent pathways to the PVN . In addition , the prominent stimulatory action of PRL on the P29323 /MAPK pathway in the hypothalamic PVN and supraoptic nucleus is likely to mediate neuroplasticity of the neuroendocrine system during lactation . Targets of transcriptional regulation by two distinct type I receptors for transforming growth factor-beta in human umbilical vein endothelial cells . Transforming growth factor-beta ( TGF-beta ) plays a crucial role in vascular development and homeostasis by regulating many transcriptional targets . P36897 ( P36897 ) is a P36897 expressed in various TGF-beta-responsive cells . In contrast , P37023 functions as a P36897 in endothelial cells , and is responsible for human hereditary hemorrhagic telangiectasia ( DB04865 ) type II . P36897 and P37023 mediate TGF-beta signals through distinct Smad proteins , i.e. , Q15796 / P84022 and Q15797 / Q99717 , respectively . To identify target genes of P37023 and P36897 in endothelial cells , we conducted oligonucleotide microarray analysis . Human umbilical vein endothelial cells ( HUVEC ) were infected with recombinant adenoviruses carrying a constitutively active form of P37023 or P36897 . P36897 inhibited the proliferation , network formation , and tube formation of HUVEC and induced their apoptosis , whereas P37023 did not exhibit significant effects on HUVEC in vitro . mRNAs were extracted from HUVEC and used for hybridization of oligonucleotide arrays representing approximately 7,000 human genes . Northern blot and quantitative real-time polymerase chain reaction ( PCR ) analyses were also performed for some of these genes , confirming the validity of this microarray analysis . We found that P37023 specifically upregulated O43541 , O15105 , Id1 , Id2 , endoglin , P42224 , and interleukin 1 receptor-like 1 . P36897 , in contrast , upregulated P49763 , SM22alpha , connexin 37 , betaIG-H3 , and Q14766 . P37023 downregulated Q15797 , P61073 , P20827 , and plakoglobin , whereas P36897 downregulated claudin 5 and integrin beta(5) . These results revealed some new targets of TGF-beta in endothelial cells , and differences in transcriptional regulation patterns between P37023 and P36897 . DB04868 : a phenylamino-pyrimidine derivative with activity against P11274 - P00519 , P10721 and P09619 kinases . The P11274 - P00519 kinase inhibitor imatinib mesylate is currently the standard therapy for patients with chronic myeloid leukemia ( CML ) . However , mutations within the P00519 kinase domain interfering with drug binding have been identified as the main mechanism of resistance to imatinib . Multiple distinct P11274 - P00519 kinase mutant isoforms conferring varying degrees of resistance to tyrosine kinase inhibitors have been reported . DB04868 is a tyrosine kinase inhibitor 30-fold more potent than imatinib against P11274 - P00519 kinase . DB04868 is active against a wide range of imatinib-resistant P11274 - P00519 mutant isoforms , except for T315I . Results from Phase II studies of nilotinib for patients with CML after failure or intolerance to imatinib therapy have shown a favorable toxicity profile and confirmed the high efficacy of nilotinib in this setting . Studies addressing the activity of nilotinib in newly-diagnosed patients with CML are underway . Furthermore , nilotinib is a potent inhibitor of P10721 and P09619 kinases . Here , we review the preclinical development of nilotinib and the activity of this agent in patients with CML and in tumors driven by P10721 and/or P09619 mutant kinases , such as gastrointestinal stromal tumors and some forms of clonal hypereosinophilia . cDNA array analysis of cytobrush-collected normal and malignant cervical epithelial cells : a feasibility study . Analysis of gene expression pattern is a useful approach to evaluating the biological behavior and clinical outcome of several human malignancies . Differentially expressed genes in malignant squamous cervical cells and the feasibility of gene expression profiling on squamous cervical cells obtained from cervical swabs were investigated . Cervical squamous cells from three women with high-risk human papilloma virus ( HR-HPV ) positive invasive squamous cervical carcinoma and from three HPV-negative women with normal ectocervical smears were analyzed with cDNA array . Immunoblot analysis was performed to detect the proteins corresponding to the highest upregulated genes with cDNA array . mRNA expression of P04626 , P10721 , P17948 , P04198 , DB01367 , CDKN2A , P24385 , P15531 , P22392 , MET , P21781 , P21802 , and P42224 was increased in malignant samples . Several expressed genes associated with antiapoptosis ( such as P10415 ) , cell structuring , or cell attachment were also upregulated in carcinoma cells . Decreased gene expression was observed for members of the transforming growth factor receptor superfamily ( TGF ) and integrin family , interleukin 1 ( IL1 ) , and insulin-like growth factor binding proteins ( IGFBPs ) . This study shows the feasibility of gene expression profiling of cervical squamous cells obtained with cytobrushes by identifying a characteristic gene expression pattern that clearly distinguishes between malignant and normal cervical epithelia of squamous type . We hypothesize that this noninvasive technique could be used in the evaluation of ambiguous Papanicolaou ( PAP ) smears . Simultaneous inhibition of MEK and P11802 leads to potent apoptosis in human melanoma cells . ABSTRACT Deregulation of DB01367 -RAF-MEK- P29323 and P42771 -cycylin D: P11802 /6-RB pathways is important for melanoma development . Chemotherapeutic agents targeting both pathways were developed but results of clinical studies with monotherapies were disappointing . We examined the effect of co-targeting both pathways with MEK inhibitor PD98059 and P11802 inhibitor 219476 on human melanoma cells lines , and found that combinatorial treatment dramatically increased apoptosis compared to the single agent treatment . The apoptosis was associated with downregulation of P10415 , Q07817 , O15392 , and upregulation of O43521 . Our results indicate that simultaneously targeting P29323 and RB pathways is a promising strategy for melanoma treatment and should encourage further in-depth investigations . miRNA-regulated expression of oncogenes and tumor suppressor genes in the cisplatin-inhibited growth of K562 cells . To explore the mechanism of apoptosis induced by cisplatin , the expression of microRNAs ( miRNAs ) and regulating genes in K562 cells was analyzed using reverse transcription PCR , quantitative real-time PCR and enzyme-linked immunosorbent assays . Our results showed that miR-16 , miR-34a-c , miR-17-5p and miR-125 were up-regulated , and their associated oncogenes ( P10415 , Q01094 and O00716 , respectively ) were down-regulated after cisplatin treatment . We also showed that miR-106 and miR-150 were down-regulated while their target genes ( P06400 and P04637 , respectively ) were up-regulated after cisplatin treatment . Moreover , miR-16 , miR-34a-c and miR-17-5p proved to be upstream factors , regulating the expression of P10415 , Q01094 and O00716 , respectively . The oncogene O00716 was down-regulated when P06400 expression was increased after treatment with antisense oligonucleotides ( ASO ) . Similarly , P10415 and O00716 were down-regulated when P04637 expression was elevated by ASO treatment . The study demonstrated that cisplatin induces K562 cells to apoptosis by reducing miR-106 which up-regulates P06400 or by inhibiting miR-150 which increases P04637 expression . The calcineurin-nuclear factor of activated T cells signaling pathway mediates the effect of corticotropin releasing factor and urocortins on catecholamine synthesis . The biological effects of the P06850 ( CRF ) family of neuropeptides are mediated by mobilization of [ Ca(2+) ] . Aim of the current work was to examine if the calcineurin/NFAT ( nuclear factor of activated T-cells ) signaling pathway is involved in the effect of CRF peptides in catecholamine synthesis and secretion from PC12 rat pheochromocytona cells , a model for the study of adrenal catecholamine production . PC12 cells express both types of CRF receptors . Our data are as follows : ( a ) The calcineurin inhibitor cyclosporine A ( DB00091 ) blocked norepinephrine secretion induced by ligands of either CRF type 1 ( CRF(1) ) or 2 ( CRF(2) ) receptors on PC12 cells . ( b ) Silencing O95644 expression using a selective O95644 siRNA blocked CRF(1) and CRF(2) -induced NE production . ( c ) CRF ligands induced NFAT transcriptional activity in cells transfected with a luciferase reporter construct controlled by NFAT binding elements ( NFAT-Luc ) . ( d ) DB00091 completely blocked the stimulatory effect of CRF(1) and CRF(2) ligands on NFAT activity in NFAT-Luc transfected cells . ( e ) PKA , PKC , p38-MAPK , Tpl2 , P01112 , and P31749 were crucial intermediates for both CRF(1) and CRF(2)-induced NFAT activation . Interestingly , Q02750 /2 and P27361 /2 were crucial only for the CRF(2)-induced NFAT activation . ( f ) p38-MAPK and Tpl2 were crucial intermediates for both CRF(1) and CRF(2)-induced norepinephrine production , while P31749 affected only CRF(2)-induced norepinephrine production . In conclusion , our data suggest that CRF(1) and CRF(2) ligands activate the transcription factor NFAT and its activation is prerequisite for CRF-induced catecholamine production from chromaffin cells . DB00104 -targeted liposomes loaded with CPT-11 enhanced cytotoxicity for the treatment of medullary thyroid carcinoma . Medullary thyroid carcinoma ( P04629 ) is a rare endocrine tumor that frequently metastasizes , but treatment with irinotecan ( CPT-11 ) is limited because of side effects . P04629 is known to overexpress the somatostatin receptor subtype 2 ( P30874 ) . DB00104 ( Oct ) is a somatostatin analogue that has a high binding affinity for SSTR and can be used as a tumor-targeting ligand . We prepared Oct-targeted liposomes loaded with CPT-11 using Oct-poly ( ethylene glycol ) ( PEG ) -lipid and evaluated Oct-mediated association and cytotoxicity of the liposomes with an P04629 cell line TT . The association of higher concentrations of modified Oct-targeted liposomes with TT cells was significantly higher than PEGylated liposomes and was significantly inhibited by empty Oct-targeted liposomes but not by free Oct . With exposure for 96 h , the cytotoxicity of Oct-targeted liposomal CPT-11 ( IC50 : 1.05 ± 0.47 μM ) was higher than free CPT-11 ( IC50 : 3.76 ± 0.61 μM ) or PEGylated liposomal CPT-11 ( IC50 : 3.05 ± 0.28 μM ) . In addition , empty Oct-targeted liposomes showed significantly higher cytotoxicity than empty nontargeted liposomes at a concentration where free Oct did not show cytotoxicity , suggesting that Oct as a ligand showed cytotoxicity . Moreover , Oct-targeted liposomal CPT-11 led to significantly higher antitumor activity and prolonged the survival time compared with nontargeted liposomal and free CPT-11 at a one-third dose and lower administration times with free CPT-11 . These findings indicated that Oct-targeted liposomes loaded with CPT-11 may offer considerable potential for P04629 chemotherapy because cytotoxicity of both CPT-11 and Oct was enhanced by effective cellular uptake via P30874 . BMP receptor-integrin interaction mediates responses of vascular endothelial Q15797 /5 and proliferation to disturbed flow . BACKGROUND : Vascular endothelial cells ( ECs ) are constantly exposed to blood flow-induced shear stress . Our previous study demonstrated that disturbed flow with low and oscillatory shear stress ( OSS ) induces bone morphogenetic protein receptor ( BMPR ) -specific Q15797 /5 activation in ECs , but the underlying mechanisms and the in vivo functional role of Q15797 /5 remain unclear . OBJECTIVES : Here we elucidated the molecular mechanisms by which OSS activates EC Q15797 /5 and its in vivo functional role . METHODS : Lentiviral Q99717 -specific short hairpin RNA ( Lenti-shSmad5 ) was constructed and intra-arterially injected into the lumen of stenosed abdominal aorta in bromodeoxyuridine-infused rats . Co-immunoprecipitation and in situ proximity ligation assays were performed on ECs exposed to OSS ( 0.5 ± 4 dynes/cm(2) ) in a parallel-plate flow chamber to investigate BMPR-integrin interactions and their regulatory role in OSS-activation of EC Q15797 /5 . RESULTS : Intra-arterial administration of Lenti-shSmad5 inhibited bromodeoxyuridine uptake of ECs at post-stenotic sites , where disturbed flow with OSS occurs . OSS induced sustained BMPRIB-αv β3 integrin association in ECs , which was mediated by the intracytoplasmic kinase domain of BMPRII and subsequently activated the Shc/focal adhesion kinase ( Q05397 ) /extracellular signal-regulated kinase ( P29323 ) cascade , leading to Q15797 /5 activation . This OSS-activation of Q15797 /5 induced its association with and activation of runt-related transcription factor-2 ( Runx2 ) , leading to activations of mammalian target of rapamycin ( P42345 ) and p70S6 kinase ( p70S6K ) , a pathway critical for EC proliferation in response to OSS . CONCLUSIONS : Oscillatory shear stress induces synergistic interactions between specific BMPRs and integrin to activate Q15797 /5 through the Shc/ Q05397 / P29323 pathway , which leads to the activation of the Runx2/ P42345 /p70S6K pathway to promote EC proliferation . P10275 rediscovered : the new biology and targeting the androgen receptor therapeutically . Discoveries over the past decade suggest that castration-resistant prostate cancer ( CRPC ) is sensitive , but not resistant to , further manipulation of the androgen-androgen receptor ( AR ) axis . Several new therapies that target this axis have demonstrated clinical activity . In this article , preclinical and clinical findings occurring in the field of AR-targeted therapies are reviewed . Reviews of scientific and clinical development are divided into those occurring prereceptor ( androgen production and conversion ) and at the level of the receptor ( AR aberrations and therapies targeting AR directly ) . Intracrine androgen production and AR amplification , among others , are among the principal aberrancies driving CRPC growth . Phase III data with abiraterone acetate and phase II data with DB08899 , along with other similar therapies , confirm for the clinician that the scientific findings related to persistent AR signaling in a castrate milieu can be harnessed to produce significant clinical benefit for patients with the disease . Studies aimed at optimizing the timing of their use and exploring the mechanisms of resistance to these therapies are under way . The clinical success of therapies that directly target androgen synthesis as well as the most common aberrancies of the AR confirm that prostate cancer retains dependence on AR signaling , even in the castrate state . Reactive oxygen species , DNA damage , and error-prone repair : a model for genomic instability with progression in myeloid leukemia ? Myelodysplastic syndromes ( P43034 ) comprise a heterogeneous group of disorders characterized by ineffective hematopoiesis , with an increased propensity to develop acute myelogenous leukemia ( AML ) . The molecular basis for P43034 progression is unknown , but a key element in P43034 disease progression is loss of chromosomal material ( genomic instability ) . Using our two-step mouse model for myeloid leukemic disease progression involving overexpression of human mutant P01111 and P10415 genes , we show that there is a stepwise increase in the frequency of DNA damage leading to an increased frequency of error-prone repair of double-strand breaks ( DSB ) by nonhomologous end-joining . There is a concomitant increase in reactive oxygen species ( ROS ) in these transgenic mice with disease progression . Importantly , P63000 , an essential component of the ROS-producing NADPH oxidase , is downstream of DB01367 , and we show that ROS production in P01111 / P10415 mice is in part dependent on P63000 activity . DNA damage and error-prone repair can be decreased or reversed in vivo by N-acetyl cysteine antioxidant treatment . Our data link gene abnormalities to constitutive DNA damage and increased DSB repair errors in vivo and provide a mechanism for an increase in the error rate of DNA repair with P43034 disease progression . These data suggest treatment strategies that target DB01367 / P31749 pathways and ROS production in human P43034 /AML . P62942 , the 12-kDa FK506-binding protein , is a physiologic regulator of the cell cycle . P62942 , the 12-kDa FK506-binding protein , is a ubiquitous abundant protein that acts as a receptor for the immunosuppressant drug FK506 , binds tightly to intracellular calcium release channels and to the transforming growth factor beta ( TGF-beta ) type I receptor . We now demonstrate that cells from P62942 -deficient ( P62942 (-/-) ) mice manifest cell cycle arrest in G(1) phase and that these cells can be rescued by P62942 transfection . This arrest is mediated by marked augmentation of P38936 ( P38936 /CIP1) levels , which can not be further augmented by TGF-beta1 . The P38936 up-regulation and cell cycle arrest derive from the overactivity of TGF-beta receptor signaling , which is normally inhibited by P62942 . Cell cycle arrest is prevented by transfection with a dominant-negative TGF-beta receptor construct . TGF-beta receptor signaling to gene expression can be mediated by SMAD , p38 , and P29323 / Q96HU1 kinase ( extracellular signal-regulated kinase/mitogen-activated protein kinase ) pathways . SMAD signaling is down-regulated in P62942 (-/-) cells . Inhibition of P29323 / Q96HU1 kinase fails to affect P38936 up-regulation . By contrast , activated phosphorylated p38 is markedly augmented in P62942 (-/-) cells and the P38936 up-regulation is prevented by an inhibitor of p38 . Thus , P62942 is a physiologic regulator of cell cycle acting by normally down-regulating TGF-beta receptor signaling . Q96RP3 is expressed in human pregnant myometrial cells and regulates myosin light chain phosphorylation : potential role of the type-2 corticotropin-releasing hormone receptor in the control of myometrial contractility . The family of P06850 -related peptides are suggested to play important roles in the control of myometrial contractility during pregnancy and labor . In this study we investigated the expression of urocortin II ( P55089 II ) in human myometrium and its ability to phosphorylate intracellular components that can be involved in modulating myometrial contractility . Using RT-PCR and fluorescent in situ hybridization , we demonstrated that P55089 II and type-2 P06850 receptor ( Q13324 ) mRNAs were expressed in human nonpregnant and pregnant myometrium . Immunofluorescent studies confirmed protein expression of P55089 II in human pregnant myometrial cells , whereas chemical cross-linking studies with radiolabeled P55089 II confirmed the presence of Q13324 sites with an apparent molecular mass of 50 kDa . Treatment of primary human myometrial cells with P55089 II to specifically activate Q13324 resulted in a dose-dependent increase of myosin light chain ( MLC(20) ) phosphorylation . Activation of protein kinase C ( PKC ) and P27361 /2 was required for the P55089 II-induced activation of MLC(20) , because treatment of myometrial cells with inhibitors of MAPK kinase 1 ( U0126 ) and PKC ( bisindolylmaleimide ) inhibited the P55089 II-induced phosphorylation of MLC(20) . Furthermore , the P55089 II effect on MLC(20) was dependent on RhoA translocation to the membrane and subsequent activation of RhoA-associated kinase , as shown by the use of the specific inhibitors exoenzyme P01024 and Y27632 . Collectively , our data suggest a distinctive role for Q13324 - specific agonists like P55089 II in the control of myometrial contractility during human pregnancy involving sequential activation of PKC , MAPK kinase 1 , P27361 /2 , RhoA , and RhoA-associated kinase , leading to the MLC(20) phosphorylation . The role of tumor suppressor dysregulation in prostate cancer progression . P10275 activity is essential for prostate cancer development and progression . While there are classically defined roles for the retinoblastoma ( P06400 ) and p53 tumor suppressor pathways in maintenance of cell cycle control and the DNA damage response , recent studies have demonstrated a direct role of these two pathways in regulating AR expression and function . While the role of Pten deregulation in prostate cancer has provided much insight in to the mechanisms underlying prostate cancer initiation and progression , emerging roles for P06400 and p53 are likely to further expand upon our understanding of tumor suppressor/nuclear receptor interaction . As disconnecting mitogenic signaling from AR-mediated gene transcription underlies the progression to castrate resistant prostate cancer ( CRPC ) , functional inactivation of these two tumor suppressor pathways represents one mechanism through which AR protein levels can be upregulated and AR-mediated gene transcription can become aberrant . Importantly , recent advances in small molecule inhibitor design and discovery have led to the identification of agents capable of targeting these two prominent pathways and restoring the function of deregulated wild-type P06400 and p53 protein . While such agents have undergone extensive study in many solid tumor types , the additional importance of P06400 and p53 in restraining transcription of the AR gene within the prostate provides impetus for examining how loss of these two tumor suppressor proteins can facilitate transition of prostate cancers to CRPC . As will be reviewed in this article , restoration of P06400 and p53 functions are not only important in regard to shortterm cell cycle regulation and response to genomic stresses , but likely have direct implications for deregulation of the AR locus . The bone morphogenetic protein signaling pathway is upregulated in a mouse model of total parenteral nutrition . Total parenteral nutrition ( O15533 ) results in intestinal mucosal atrophic changes due to an absence of enteral nutrition ; however , the mechanisms responsible for this are not fully understood . It has been shown that bone morphogenetic protein ( BMP ) activation inhibits intestinal epithelial cell ( EC ) proliferation . Therefore , we hypothesized that the BMP pathway could be upregulated by O15533 . To address this , we randomly assigned mice to receive O15533 or to be enterally fed ( control ) for 7 d . Mucosal EC isolates were harvested from the entire length of small intestine for RNA and protein measurements . Q8N1N2 -thickness , mid-small bowel was processed for histological examination . O15533 increased the abundance of P12643 , P12644 , and Q13873 at the RNA and protein levels . Phosphorylation of Q15797 , Q99717 , and Smad8 also was greater in the O15533 group than in the control , which helped to confirm activation of this pathway . Interestingly , the O15533 and control groups did not differ in the mRNA expression of the extracellular soluble bmp antagonists , noggin , gremlin , chordin , or follistatin . Compared to the control group , the expression of c-Myc ( cellular myelocytomatosis ) mRNA was lower , whereas the level of P38936 ( P38936 /CIP1) was greater , in the O15533 group . Because the BMP family may function through suppression of Wnt-beta-catenin signaling , this pathway was also examined . mRNA expression of Wnt 3 , Wnt5a , and the Wnt receptor Lrp5 were lower in the O15533 group compared to controls . The results suggest that the BMP signaling pathway may be involved in the development of intestinal mucosal atrophy due to O15533 administration . P10275 -induced tumor suppressor , B2CW77 , inhibits breast cancer growth and transcriptionally activates p53/p73-mediated apoptosis in breast carcinomas . P10275 ( AR ) expression by immunohistochemistry correlates with better prognosis and survival among breast cancer patients . We and others have shown that AR inhibits proliferation and induces apoptosis in breast cancer cells . However , the mechanism of AR 's anti-tumor effect in breast cancer is still not fully understood . Our recent study indicates that AR upregulates expression of tumor suppressor gene P60484 by promoter activation in breast cancer . B2CW77 , encoding B2CW77 protein , is a newly identified gene , which shares a bidirectional promoter with P60484 and is transcribed in the opposite direction . So far , the function of B2CW77 has never been studied in tumorigenesis . Here , we define B2CW77 as a tumor suppressor in breast carcinomas , which inhibits tumor growth and invasiveness . After analyzing 188 normal breast and 1247 malignant breast cancer tissues , we observed the loss of B2CW77 in multiple breast cancer subtypes and this decreased B2CW77 expression associates with tumor progression and increasing histological grade in invasive carcinomas . We characterize B2CW77 , for the first time , as a transcription factor , directly promoting the expression of P04637 and O15350 , with consequent elevated apoptosis and cell cycle arrest in breast cancer cells . We demonstrate , in vitro and in murine xenograph models , that both B2CW77 and P60484 are AR-target genes , mediating androgen-induced growth inhibition and apoptosis in breast cancer cells . Our observations suggest that B2CW77 might be used as a potential prognostic marker and novel therapy target for breast carcinomas . Genotoxicity and induction of DNA damage responsive genes by food-borne heterocyclic aromatic amines in human hepatoma HepG2 cells . Heterocyclic aromatic amines ( HAAs ) are potential human carcinogens formed in well-done meats and fish . The most abundant are 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine ( PhIP ) , 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline ( MeIQx ) , 2-Amino-3,4,8-trimethyl-3H-imidazo[4,5-f]quinoxaline ( 4,8-DiMeIQx ) and 2-Amino-3-methyl-3H-imidazo[4,5-f]quinoline ( IQ ) . HAAs exert genotoxic activity after metabolic transformation by CYP1A enzymes , that is well characterized , however the genomic and intervening responses are not well explored . We have examined cellular and genomic responses of human hepatoma HepG2 cells after 24h exposure to HAAs . Comet assay revealed increase in formation of DNA strand breaks by PhIP , MeIQx and IQ but not 4,8-DiMeIQx , whereas increased formation of micronuclei was not observed . The four HAAs up-regulated expression of genes encoding metabolic enzymes P04798 , P05177 and P22309 and expression of P04637 and its downstream regulated genes P38936 , GADD45α and Q07812 . Consistent with the up-regulation of P38936 and GADD45α the cell-cycle analysis showed arrest in S-phase by PhIP and IQ , and in P55008 -phase by 4,8-DiMeIQx and MeIQx . The results indicate that upon exposure to HAAs the cells respond with the cell-cycle arrest , which enables cells to repair the damage or eliminate them by apoptosis . However , elevated expression of P10415 and down-regulation of Q07812 may indicate that HAAs could suppress apoptosis meaning higher probability of damaged cells to survive and mutate . P42892 and β-arrestins exert spatiotemporal control of DB05875 -induced inflammatory signals . Although the intracellular trafficking of G protein-coupled receptors controls specific signaling events , it is unclear how the spatiotemporal control of signaling contributes to complex pathophysiological processes such as inflammation . By using bioluminescence resonance energy transfer and superresolution microscopy , we found that DB05875 ( SP ) induces the association of the neurokinin 1 receptor ( P25103 ) with two classes of proteins that regulate SP signaling from plasma and endosomal membranes : the scaffolding proteins β-arrestin ( βARRs ) 1 and 2 and the transmembrane metallopeptidases ECE-1c and ECE-1d . In HEK293 cells and non-transformed human colonocytes , we observed that G protein-coupled receptor kinase 2 and β P49407 /2 terminate plasma membrane Ca(2+) signaling and initiate receptor trafficking to endosomes that is necessary for sustained activation of ERKs in the nucleus . βARRs deliver the SP- P25103 endosomes , where P42892 associates with the complex , degrades SP , and allows the P25103 , freed from βARRs , to recycle . Thus , both P42892 and βARRs mediate the resensitization of P25103 Ca(2+) signaling at the plasma membrane . Sustained exposure of colonocytes to SP activates NF-κB and stimulates P10145 secretion . This proinflammatory signaling is unaffected by inhibition of the endosomal P29323 pathway but is suppressed by P42892 inhibition or β P32121 knockdown . Inhibition of protein phosphatase 2A , which also contributes to sustained P25103 signaling at the plasma membrane , similarly attenuates P10145 secretion . Thus , the primary function of βARRs and P42892 in SP-dependent inflammatory signaling is to promote resensitization , which allows the sustained P25103 signaling from the plasma membrane that drives inflammation . Induction of apoptosis by a dominant negative H- DB01367 mutant ( 116Y ) in K562 cells . Recent extensive work on apoptosis has begun to reveal its molecular mechanisms . Several genes that regulate apoptosis have been identified . Among them , the P10415 gene is considered to be an important gene that inhibits apoptosis . However , there must be other genes , yet to be identified , which suppress apoptosis . It has been suggested that the activation of DB01367 function by P11274 - P00519 fusion protein in chronic myelogenous leukemia may be an important mechanism in the P11274 - P00519 mediated transformation . Therefore , in this study we have investigated whether the suppression of endogenous H- DB01367 function inhibits the P11274 - P00519 mediated transforming activity in a K562 human chronic myelogenous leukemia cell line . The induced expression of a dominant negative v-H- DB01367 mutant ( 116Y ) in K562 cells has resulted in cell death . The morphological characteristics and the detection of fragmented DNA by gel electrophoresis in the dead cells have revealed that this cell death is apoptosis . These results directly indicate that the DB01367 gene as well as the P10415 gene has an ability to suppress apoptosis . Dysregulated P04629 signalling is a therapeutic target in Q9NQC7 defective tumours . Individuals with germline mutations in the tumour-suppressor gene Q9NQC7 are at high risk of developing disfiguring cutaneous appendageal tumours , the defining tumour being the highly organised cylindroma . Here , we analysed Q9NQC7 mutant tumour genomes by array comparative genomic hybridisation and gene expression microarray analysis . Q9NQC7 mutant tumours were characterised by an absence of copy-number aberrations apart from LOH chromosome 16q , the genomic location of the Q9NQC7 gene . Gene expression profiling of Q9NQC7 mutant tumours showed dysregulated tropomyosin kinase ( P04629 ) signalling , with overexpression of Q16620 and Q16288 in tumours when compared with perilesional skin . Immunohistochemical analysis of a tumour microarray showed strong membranous Q16620 and Q16288 staining in cylindromas , as well as elevated levels of P29323 phosphorylation and P10415 expression . Membranous Q16288 overexpression was also observed in 70 % of sporadic BCCs . RNA interference-mediated silencing of Q16620 and Q16288 , as well as treatment with the small-molecule P04629 inhibitor lestaurtinib , reduced colony formation and proliferation in 3D primary cell cultures established from Q9NQC7 mutant tumours . These results suggest that P04629 inhibition could be used as a strategy to treat tumours with loss of functional Q9NQC7 . P04150 antagonism disrupts the reconsolidation of social reward-related memories in rats . Reconsolidation is the process whereby consolidated memories are destabilized upon retrieval and restabilized to persist for later use . Although the neurobiology of the reconsolidation of both appetitive and aversive memories has been intensively investigated , reconsolidation of memories of physiologically relevant social rewards has received little attention . Social play , the most characteristic social behaviour displayed by young mammals , is highly rewarding , illustrated by the fact that it can induce conditioned place preference ( CPP ) . Here , we investigated the role of signalling mechanisms implicated in memory processes , including reconsolidation , namely glucocorticoid , mineralocorticoid , DB01221 glutamatergic and P21554 cannabinoid receptors , in the reconsolidation of social play-induced CPP in rats . Systemic treatment with the glucocorticoid receptor antagonist mifepristone before , but not immediately after , retrieval disrupted the reconsolidation of social play-induced CPP . DB00834 did not affect social play-induced CPP in the absence of memory retrieval . Treatment with the DB01221 receptor antagonist MK-801 modestly affected the reconsolidation of social play-induced CPP . However , the reconsolidation of social play-induced CPP was not affected by treatment with the mineralocorticoid and P21554 cannabinoid receptor antagonists spironolactone and rimonabant , respectively . We conclude that glucocorticoid neurotransmission mediates the reconsolidation of social reward-related memories in rats . These data indicate that the neural mechanisms of the reconsolidation of social reward-related memories only partially overlap with those underlying the reconsolidation of other reward-related memories . An association analysis of circadian genes in anxiety disorders . BACKGROUND : The mammalian circadian system is responsible for controlling daily oscillations in physiology and behavior . Circadian genes contribute to the sleep-wake cycle and mood , and because patients with anxiety disorder often suffer from sleep disturbances , we hypothesized that variants in circadian-clock-related genes might predispose to human anxiety disorders as well . We tested this hypothesis with a genetic association analysis . METHODS : We analyzed 131 single nucleotide polymorphisms from 13 circadian-clock-related genes . The study sample consisted of 321 individuals diagnosed with an anxiety disorder and 653 matched healthy controls from a Finnish population-based cohort . RESULTS : Single nucleotide polymorphisms in two genes showed some evidence for association to social phobia : in Q8WYA1 rs2306073 ( p = .0099 ) and in P14416 rs7131056 ( p = .0084 ) . P10415 rs12454712 ( p = .0029 ) and P14416 rs4245146 ( p = .0010 ) showed evidence for association to generalized anxiety disorder , whereas rs2463107 ( p = .0064 ) in Q96IZ0 and rs4245146 ( p = .0029 ) in P14416 showed evidence for association to the pooled group of all anxiety disorders . Findings in P14416 became stronger when only anxiety disorder cases with comorbid alcohol use disorder were considered . CONCLUSIONS : Genes contributing to circadian rhythms might also play a role in the genetic predisposition to anxiety disorders . In addition , our study provides further support for the association of P14416 to comorbid anxiety and alcohol use disorder . DB02546 and bortezomib synergistically cause ubiquitinated protein accumulation in prostate cancer cells . PURPOSE : Protein ubiquitination is a novel strategy used to treat malignancies . We investigated whether the histone deacetylase inhibitor vorinostat ( Cayman Chemical , Ann Arbor , Michigan ) and the proteasome inhibitor bortezomib ( LC Laboratories , Woburn , Massachusetts ) would synergistically cause the accumulation of ubiquitinated proteins in prostate cancer cells . MATERIALS AND METHODS : LNCaP , PC-3 and DU 145 cells ( ATCC™ ) were treated with vorinostat and/or bortezomib . Cell viability and induction of apoptosis were assessed . In vivo efficacy was evaluated in a murine subcutaneous tumor model using PC-3 cells . The influence of androgen receptor expression on bortezomib efficacy was examined using RNA interference . Changes in the expression of ubiquitinated proteins , cell cycle associated proteins and acetylated histone were evaluated . RESULTS : P10275 expression seemed to decrease bortezomib activity . PC-3 and DU 145 cells were more susceptible to bortezomib than LNCaP cells and the silencing of androgen receptor expression in LNCaP cells enhanced bortezomib activity . DB02546 and bortezomib synergistically induced apoptosis , inhibited prostate cancer cell growth and suppressed tumor growth in a murine xenograft model . The combination decreased cyclin D1 and cyclin-dependent kinase 4 expression , and increased P38936 expression . The combination synergistically caused the accumulation of ubiquitinated proteins and histone acetylation . This histone acetylation was a consequence of the accumulation of ubiquitinated proteins . CONCLUSIONS : DB02546 and bortezomib inhibit the growth of prostate cancer cells synergistically by causing ubiquitinated proteins to accumulate in cells . The current study provides a framework for testing the combination in patients with advanced prostate cancer . Targeting eIF4GI translation initiation factor affords an attractive therapeutic strategy in multiple myeloma . BACKGROUND : Deregulation of protein synthesis is integral to the malignant phenotype and translation initiation is the rate limiting stage . Therefore , eIF4F translation initiation complex components are attractive therapeutic targets . METHODS : Protein lysates of myeloma cells ( cell lines/patients ' bone marrow samples ) untreated/treated with bevacizumab were assayed for eIF4GI expression , regulation ( P15559 /proteosome dependent fragmentation ) ( WB , DB00266 , qPCR ) and targets (WB). eIF4GI was inhibited by knockdown and 4EGI-1 . Cells were tested for viability ( ELISA ) , death ( FACS ) and eIF4GI targets ( WB ) . RESULTS : Previously , we have shown that manipulation of P15692 in myeloma cells attenuated P06730 dependent translation initiation . Here we assessed the significance of eIF4GI to MM cells . We demonstrated increased expression of eIF4GI in myeloma cells and its attenuation upon P15692 inhibition attributed to elevated P15559 /proteasome dependent fragmentation and diminished mRNA levels . Knockdown of eIF4GI was deleterious to myeloma cells phenotype and expression of specific molecular targets ( Q99717 /ERα/HIF1α/c-Myc ) . Finally , we showed that the small molecule 4EGI-1 inhibits eIF4GI and causes a reduction in expression of its molecular targets in myeloma . CONCLUSION : Our findings substantiate that translation initiation of particular targets in MM is contingent on the function of eIF4GI , critical to cell phenotype , and mark it as a viable target for pharmacological intervention . AM251 induces apoptosis and G2/M cell cycle arrest in A375 human melanoma cells . Human cutaneous melanoma is an aggressive and chemotherapy-resistant type of cancer . AM251 is a cannabinoid type 1 ( P21554 ) receptor antagonist/inverse agonist with off-target antitumor activity against pancreatic and colon cancer cells . The current study aimed to characterize the in-vitro antimelanoma activity of AM251 . The P15056 V600E mutant melanoma cell line , A375 , was used as an in-vitro model system . Characterization tools included a cell viability assay , nuclear morphology assessment , gene expression , western blot , flow cytometry with P08758 -FITC/7-AAD double staining , cell cycle analyses , and measurements of changes in intracellular DB02527 and calcium concentrations . AM251 exerted a marked cytotoxic effect against A375 human melanoma cells with potency comparable with that observed for cisplatin without significant changes in the human dermal fibroblasts viability . AM251 , at a concentration that approximates the IC50 , downregulated genes encoding antiapoptotic proteins ( P10415 and survivin ) and increased transcription levels of proapoptotic Q07812 , induced alteration of P08758 reactivity , DNA fragmentation , chromatin condensation in the cell nuclei , and G2/M phase arrest.AM251 also induced a 40 % increase in the basal DB02527 levels , but it did not affect intracellular calcium concentrations . The involvement of Q9Y2T6 , O75762 , and P35354 in the AM251 mechanism of action was excluded . The combination of AM251 with celecoxib produced a synergistic antitumor activity , although the mechanism underlying this effect remains to be elucidated . This study provides the first evidence of a proapoptotic effect and G2/M cell cycle arrest of AM251 on A375 cells . This compound may be a potential prototype for the development of promising diarylpyrazole derivatives to be evaluated in human cutaneous melanoma . Molecular pathways : the basis for rational combination using MEK inhibitors in P01116 -mutant cancers . Mutations in DB01367 oncogenes are frequently observed in human cancers , and the mutations result in activation of the DB01367 -RAF-MEK- P29323 pathway , leading to cell proliferation and survival . The pathway is , therefore , a potent therapeutic target in the DB01367 -mutant cancers . MEK inhibitors can specifically block the pathway and are one of the key types of drugs for the treatment of the DB01367 -mutant cancers . As DB01367 proteins activate other downstream signaling proteins in addition to the DB01367 -RAF-MEK- P29323 pathway , combination therapeutic approaches with MEK inhibitors are also being evaluated . Moreover , MEK inhibitors can arrest cancer cells in P55008 phase and repress prosurvival Bcl2 family proteins such as Q07820 and P10415 /BCLXL , and increase expression of Bim , a proapoptotic BH3-only family protein . This mechanism may explain the efficacy of the combination of MEK inhibitors with cytotoxic agents or other targeted inhibitors . A better understanding of the pathway will help us with development of rational combinations for the treatment of the DB01367 -mutant cancers . P06401 activation of extranuclear signaling pathways in regulating p53 expression in vascular endothelial cells . We previously showed that progesterone ( P4 ) inhibited the proliferation of human umbilical vein endothelial cells ( HUVECs ) through a p53-dependent pathway . Now we investigated further the molecular mechanism underlying the hormone activity . In cultured HUVECs , P4 increased the protein levels of phosphorylated Src ( p-Src ) , P04049 , and P29323 . The levels of p-Src and p-Src-progesterone receptor complex in HUVECs were increased by P4 treatment . These effects were blocked by pretreatment with a progesterone receptor antagonist , DB00834 . The P4-induced increase in p53 transactivity was abolished by pretreatment with Src kinase inhibitors . Moreover , administration with cSrc antisense oligonucleotide prevented the P4-induced increases of the levels of p53 mRNA and protein . These data suggest that P4-induced up-regulation of p53 might be mediated through activation of cSrc . Pretreatment with Src kinase inhibitors also prevented P4-induced membrane translocation of Kras and increases of the protein levels of phosphorylated Raf and phosphorylated P29323 . Transfection with dominant-negative P28482 prevented the P4-induced increases of protein level and promoter activity of p53 and a decrease of thymidine incorporation . P4 also increased nuclear factor-κB ( NF-κB ) nuclear translocation and NF-κB binding onto the p53 promoter . These effects were abolished by pretreatment with P29323 inhibitors . The P4-induced up-regulation of the p53 promoter activity was prevented by preadministration with dominant-negative P28482 or NF-κB inhibitors . Taken together , our data suggest that the cSrc/Kras/ P04049 / P28482 /NF-κB signaling pathway contributes to the P4-induced up-regulation of p53 in HUVECs . These findings highlight progesterone receptor activation of extranuclear signaling pathways in regulating p53 and cell cycle progression in HUVECs . Generation of Epstein-Barr virus-specific cytotoxic T lymphocytes resistant to the immunosuppressive drug tacrolimus ( FK506 ) . Adoptive transfer of autologous Epstein-Barr virus-specific cytotoxic T lymphocytes ( EBV-CTLs ) to solid organ transplant ( SOT ) recipients has been shown safe and effective for the treatment of EBV-associated posttransplantation lymphoproliferative disorders ( PTLDs ) . SOT recipients , however , require the continuous administration of immunosuppressive drugs to prevent graft rejection , and these agents may significantly limit the long-term persistence of transferred EBV-CTLs , precluding their use as prophylaxis . DB00864 ( FK506 ) is one of the most widely used immunosuppressive agents in SOT recipients , and its immunosuppressive effects are largely dependent on its interaction with the 12-kDa FK506-binding protein ( P62942 ) . We have knocked down the expression of P62942 in EBV-CTLs using a specific small interfering RNA ( siRNA ) stably expressed from a retroviral vector and found that P62942 -silenced EBV-CTLs are FK506 resistant . These cells continue to expand in the presence of the drug without measurable impairment of their antigen specificity or cytotoxic activity . We confirmed their FK506 resistance and anti-PTLD activity in vivo using a xenogenic mouse model , suggesting that the proposed strategy may be of value to enhance EBV-specific immune surveillance in patients at high risk of PTLD after transplantation . The BH3 mimetic DB05764 synergizes with the Q02750 /2 inhibitor selumetinib/AZD6244 to promote O43521 -dependent tumour cell death and inhibit acquired resistance . Tumour cells typically exhibit a G(1) cell cycle arrest in response to the Q02750 /2 [ mitogen-activated protein kinase/ P29323 ( extracellular-signal-regulated kinase ) kinase 1/2 ] inhibitor selumetinib , but do not die , and thus they acquire resistance . In the present study we examined the effect of combining selumetinib with the BH3 [ P10415 ( B-cell lymphoma 2 ) homology domain 3 ] -mimetic P10415 inhibitor DB05764 . Although either drug alone caused little tumour cell death , the two agents combined to cause substantial caspase-dependent cell death and inhibit long-term clonogenic survival of colorectal cancer and melanoma cell lines with P15056 (V600E) or DB01367 mutations . This cell death absolutely required Q07812 ( P10415 -associated X protein ) and was inhibited by RNAi ( RNA interference ) -mediated knockdown of O43521 ( P10415 -interacting mediator of cell death ) in the P15056 (V600E)-positive COLO205 cell line . When colorectal cancer cell lines were treated with selumetinib plus DB05764 we observed a striking reduction in the incidence of cells emerging with acquired resistance to selumetinib . Similar results were observed when we combined DB05764 with the P15056 (V600E)-selective inhibitor PLX4720 , but only in cells expressing P15056 (V600E) . Finally , cancer cells in which acquired resistance to selumetinib arises through P15056 (V600E) amplification remained sensitive to DB05764 , whereas selumetinib-resistant HCT116 cells ( P01116 (G13D) amplification ) were cross-resistant to DB05764 . Thus the combination of a P10415 inhibitor and an P27361 /2 pathway inhibitor is synthetic lethal in P27361 /2-addicted tumour cells , delays the onset of acquired resistance and in some cases overcomes acquired resistance to selumetinib . [ Role of neurokinin-1 receptor in lung injury in rats with acute necrotizing pancreatitis ] . OBJECTIVE : To investigate the expression of neurokinin-1 receptor ( P25103 ) in the lung tissue , and the relationship between expression of P25103 and lung injury in rats with acute necrotizing pancreatitis ( P01160 ) . METHODS : One hundred and twenty adult Sprague-Dawley rats were randomly divided into P01160 and control groups . Animals in group P01160 were induced by the retrograde intraductal infusion of 5 % sodium taurocholate ( 0.1 ml/kg ) , and animals in normal control group received laparotomy only . The accumulation of polymorphonuclear leukocytes in lung tissues was measured with myeloperoxidase ( P05164 ) assay . Lung endothelial barrier destruction was measured by lung capillary permeability ( LCP ) . Reverse transcription polymerase chain reaction ( RT-PCR ) was used to determine the mRNA expression of P25103 , western blot analysis was used to determine P25103 protein expression levels , and immunohistochemistry was used to localize expression site of P25103 . RESULTS : P25103 mRNA level was enhanced in the lung of P01160 compared with normal control group . Western blot analysis showed overexpression of P25103 protein level exited in P01160 group . Statistical analysis revealed correlation between P25103 mRNA and P05164 ( r=0.83 , P < 0.01 ) and LCP ( r=0.79 , P < 0.01 ) respectively . With immunohistochemistry staining , moderate to strong P25103 immunoreactivity was localized to alveolar membrane , I epithelium , II epithelium and polymorphonuclear leukocytes in the lung of P01160 . CONCLUSION : In P01160 , overexpression of P25103 contributes to disturbance of neuropeptides loop , resulting in aggregation of neutrophilic granulocyte and promoting deterioration of lung injury . Linkage of cytokine genes to rheumatoid arthritis . Evidence of genetic heterogeneity . OBJECTIVE : To investigate linkage of candidate disease susceptibility genes to rheumatoid arthritis ( RA ) in affected sibling pair families stratified for specific clinical features . METHOD : Two hundred RA affected sibling pair families were genotyped for informative microsatellite markers mapping within or less than 3cM from : P27352 alpha , P27352 gamma , P27352 beta , IL1 alpha , IL1 beta , P14778 , P60568 , P05231 , Q01344 , IL8R , P10415 , P29965 , NOS3 , P49279 , alpha 1 anti-trypsin , and alpha 1 anti-chymotrypsin , using fluorescence based automated technology . Linkage was examined by defining allele sharing sibling pairs . This was assessed by maximum likelihood-inheritance by descent methods . RESULTS : An increase in allele sharing was seen for Q01344 in female sibling pairs ( LOD 0.91 , p = 0.03 ) , for P27352 gamma in sibling pairs with an affected male ( LOD 0.96 , p = 0.03 ) and most significantly for P60568 in sibling pairs where one or both were persistently seronegative ( LOD 1.05 , p = 0.02 ) . CONCLUSION : Weak evidence of linkage of RA to Q01344 , IFN gamma , and P60568 has been detected in clinical subsets of sibling pairs suggesting that RA is a genetically heterogeneous disease . Comparison of imatinib , dasatinib , nilotinib and INNO-406 in imatinib-resistant cell lines . We compared the growth-inhibitory effects and inhibition profile of the P12931 family kinases ( SFKs ) of imatinib , dasatinib , nilotinib and INNO-406 . Dasatinib exhibited the strongest potency against P11274 - P00519 with little selectivity over SFKs . DB04868 exhibited a weaker affinity than the other inhibitors , but was highly specific for P00519 and may be useful for the treatment of P-glycoprotein overexpressing leukemic cells . INNO-406 had an intermediate affinity for P11274 - P00519 between that of dasatinib and nilotinib , and inhibited only SFKs P06239 and P07948 among SFKs . Both nilotinib and INNO-406 were potent inhibitors of the dasatinib-resistant T315A , F317L and F317V P11274 - P00519 mutations . Association between severe toxicity of nilotinib and P22309 polymorphisms in Japanese patients with chronic myelogenous leukemia . BACKGROUND : DB04868 is a P11274 - P00519 kinase inhibitor approved for the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia ( CML ) . The P22309 ( P22309 ) polymorphism P22309 *28 ( *28 ) /*28 has been linked to an increased risk of hyperbilirubinemia in patients with CML who receive nilotinib . Beside *28 , P22309 *6 ( *6 ) is another important variant allele in Japanese patients because it is associated with adverse events of irinotecan , metabolized by P22309 . We retrospectively investigated the association between severe toxicity of nilotinib and P22309 polymorphisms ( *6 and*28 ) in Japanese patients with CML . PATIENTS AND METHODS : Eight patients with cytogenetically confirmed CML who were receiving nilotinib were studied to explore the association of P22309 polymorphisms with severe nilotinib-related toxicity . Genotyping analyses were determined for *6 and *28 . RESULTS : All 3 patients with the *6/*6 or *6/*28 genotype had severe toxicity , including QT interval prolongation ( grade 3 ) , elevated lipase levels ( grade 3 ) plus hyperbilirubinemia ( grade 2 ) , and anemia ( grade 3 ) plus hepatic cyst hemorrhage ( grade 2 ) in 1 patient each . Among the 5 patients with the *6/*1 or *1/*1 genotype , 1 had elevated lipase levels ( grade 3 ) and another had severe pain in the lower extremities ( grade 3 ) . CONCLUSION : These findings suggest that P22309 polymorphisms are important determinants of severe toxicity of nilotinib in Japanese patients . Cooperative Hedgehog- P00533 signaling . It has been known for many years that cooperative interactions between oncogenes ( e.g. DB01367 , MYC , P10415 ) can fuel cancer growth ( 1-5 ) , but the restricted druggability of many of those interacting cancer genes has hampered translation of combined targeting to medical cancer therapy . The identification and characterization of cooperative cancer signaling pathways amenable to medical therapy is therefore a crucial step towards the establishment of efficient targeted combination treatments urgently needed to improve cancer therapy . Here we review recent findings of our group and colleagues on the molecular mechanisms of cooperative Hedgehog/ P08151 and Epidermal Growth Factor Receptor ( P00533 ) signaling , two clinically relevant oncogenic pathways involved in the development of many human malignancies . We also discuss the possible implications of these findings for the design of a therapeutic regimen relying on combined targeting of key effectors of both pathways . [ DB00391 in the management of functional dyspepsia and delayed gastric emptying ] . DB00391 is a sulpiride isomer that exerts its prokinetic action through a dual mechanism : 1 ) as a P14416 antagonist and 2 ) as a serotonin 5HT(4) receptor agonist , conferring this drug with a cholinergic effect . At a dosage of 25mg three times daily , levosulpiride accelerates gastric and gallbladder emptying . Clinical trials have shown that this agent is more effective than placebo in reducing the symptoms of dyspepsia , while comparative studies have demonstrated that its effect is similar or superior to that of other dopamine antagonists . The safety profile of levosulpiride is good and the frequency of adverse events is similar to that of other D(2) dopamine antagonists . Therefore , this drug is a useful therapeutic option in the management of patients with functional dyspepsia , as well as in those with delayed gastric emptying . DB04868 and MEK inhibitors induce synthetic lethality through paradoxical activation of RAF in drug-resistant chronic myeloid leukemia . We show that imatinib , nilotinib , and dasatinib possess weak off-target activity against RAF and , therefore , drive paradoxical activation of P15056 and CRAF in a DB01367 -dependent manner . Critically , because DB01367 is activated by P11274 - P00519 , in drug-resistant chronic myeloid leukemia ( CML ) cells , DB01367 activity persists in the presence of these drugs , driving paradoxical activation of P15056 , CRAF , MEK , and P29323 , and leading to an unexpected dependency on the pathway . Consequently , nilotinib synergizes with MEK inhibitors to kill drug-resistant CML cells and block tumor growth in mice . Thus , we show that imatinib , nilotinib , and dasatinib drive paradoxical RAF/MEK/ P29323 pathway activation and have uncovered a synthetic lethal interaction that can be used to kill drug-resistant CML cells in vitro and in vivo . That which does not kill me makes me stronger ; combining P27361 /2 pathway inhibitors and BH3 mimetics to kill tumour cells and prevent acquired resistance . Oncogenic mutations in DB01367 or P15056 can drive the inappropriate activation of the P27361 /2 . In many cases , tumour cells adapt to become addicted to this deregulated P27361 /2 signalling for their proliferation , providing a therapeutic window for tumour-selective growth inhibition . As a result , inhibition of P27361 /2 signalling by P15056 or Q02750 /2 inhibitors is an attractive therapeutic strategy . Indeed , the first P15056 inhibitor , vemurafenib , has now been approved for clinical use , while clinical evaluation of Q02750 /2 inhibitors is at an advanced stage . Despite this progress , it is apparent that tumour cells adapt quickly to these new targeted agents so that tumours with acquired resistance can emerge within 6-9 months of primary treatment . One of the major reasons for this is that tumour cells typically respond to P15056 or Q02750 /2 inhibitors by undergoing a P55008 cell cycle arrest rather than dying . Indeed , although inhibition of P27361 /2 invariably increases the expression of pro-apoptotic P10415 family proteins , tumour cells undergo minimal apoptosis . This cytostatic response may simply provide the cell with the opportunity to adapt and acquire resistance . Here we discuss recent studies that demonstrate that combination of P15056 or Q02750 /2 inhibitors with inhibitors of pro-survival P10415 proteins is synthetic lethal for P27361 /2-addicted tumour cells . This combination effectively transforms the cytostatic response of P15056 and Q02750 /2 inhibitors into a striking apoptotic cell death response . This not only augments the primary efficacy of P15056 and Q02750 /2 inhibitors but delays the onset of acquired resistance to these agents , validating their combination in the clinic . LINKED ARTICLES : This article is part of a themed section on Emerging Therapeutic Aspects in Oncology . To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.169.issue-8 . Traps to catch unwary oncogenes . The MYC proto-oncogene has long been implicated in the control of normal cell growth and its deregulation is associated with the development of neoplasia . The MYC protein has a well-established role as a component of signal-transduction pathways promoting both proliferation and apoptosis . Because signalling pathways that drive cell death and cell proliferation are so tightly coupled , a synergy between genetic lesions leading to suppression of cell death and those promoting cell proliferation is observed during carcinogenesis . We discuss such synergy with respect to the cooperating oncogenes MYC , DB01367 and P10415 . [ The involvement of c-Abl and D40 ( Q8NG31 / Q8NG31 ) proteins in the regulation of cell proliferation and cancer ] . Although c-Abl and D40 proteins are localized predominantly in nucleus , they are involved in different cellular processes . c-Abl is a tyrosine-kinase that takes part in protein phosphorylation on tyrosine . Recently D40 has been identified as a component of outer kinetochore complex . Despite of functional differences between c-Abl and D40 proteins , they have some similarities . First , high expression levels of c-Abl and D40 were observed not only in proliferating somatic cells , such as tumors , but also in healthy human testis . The increased expression levels of c-Abl and D40 protein in spermatocytes and acrosome of spermatids indicate their role in meiosis and spermatogenesis . Second , both proteins interact with specific regions of chromatin and are involved in the regulation of cell growth and division . Third , P00519 and D40 ( Q8NG31 ) genes are involved in chromosomal translocations that subsequently form chimeric oncoproteins P11274 - P00519 , P41212 - P00519 and Q03164 - Q8NG31 in human leukaemia . Finally , both proteins interact with the tumor suppressor P06400 protein and subsequently can lead to regulation of the cell proliferation . The possible regulatory pathways that are controlled by c-Abl and D40 proteins are described here in details . Complementation by P10415 and C-HA- DB01367 oncogenes in malignant transformation of rat embryo fibroblasts . The P10415 ( B cell lymphoma/leukemia-2 ) and C-HA- DB01367 oncogenes encode membrane-associated proteins of 26 and 21 kilodaltons , respectively . Although DB01367 proteins have long been known for their ability to bind and hydrolyze GTP , recent investigations suggest that P10415 encodes a novel GTP-binding protein ( S. Haldar , C. Beatty , Y. Tsujimoto , and C. M. Croce , Nature [ London ] 342:195-198 , 1989 ) . Cotransfection of P10415 and HA- DB01367 oncogenes resulted in morphological transformation of early-passage rodent fibroblasts , rendering these cells tumorigenic in animals and enabling them to grow in semisolid medium . In contrast , cotransfection of P10415 with oncogenes that encode nuclear proteins ( E1A and C-MYC ) did not produce malignant transformation , whereas HA- DB01367 did complement with these genes . These findings suggest that proteins encoded by oncogenes such as P10415 and HA- DB01367 , although having similar subcellular locations and perhaps similar biochemical properties , can regulate distinct complementary pathways involved in cellular transformation . DB00104 and the novel multireceptor ligand somatostatin receptor agonist pasireotide ( DB06663 ) block the adrenalectomy-induced increase in mitotic activity in male rat anterior pituitary . The novel somatostatin receptor agonist pasireotide binds with high affinity to somatostatin receptors P30872 , 2 , 3 , and 5 . Acting principally through the latter , it inhibits basal and P06850 -stimulated DB01285 secretion from the AtT20 corticotroph cell line and DB01285 release from a proportion of human corticotroph adenomas both in vitro and in vivo . Data supporting an additional antiproliferative effect has led to pasireotide being explored as a potential therapy for patients with Cushing 's disease . We have compared the effects of pasireotide and octreotide on adrenalectomy-induced mitotic and apoptotic activity in the male rat anterior pituitary . Adrenalectomized rats were treated with daily sc injections of vehicle , pasireotide , or octreotide . Changes in proliferation and apoptosis were determined 2-6 d postoperatively . DB06663 and octreotide had no effect on baseline pituitary cell turnover and no measurable effects on apoptosis . However , the wave of increased mitotic activity normally seen in the pituitary after adrenalectomy was completely abolished . Nevertheless , pasireotide and octreotide did not diminish the increase in DB01285 -immunopositive cell index after adrenalectomy , indicating that cell division and differentiation of hormonally null cells in the pituitary are under independent control . In conclusion , basal cell turnover in the pituitary is not inhibited by pasireotide or octreotide . Bilateral adrenalectomy stimulates differentiation of preexisting null cells into DB01285 -positive cells . Cell division after bilateral adrenalectomy occurs in a specific subpopulation of hormonally null cells that are equally sensitive to the antiproliferative effects of pasireotide and octreotide , implicating P30874 receptors in this antimitotic response . Contribution of the kidney to metabolic clearance of atrial natriuretic peptide . To quantify the role of the kidney in whole body metabolic clearance rate ( P08235 ) from plasma of atrial natriuretic peptide ( P01160 ) , synthetic alpha-human P01160 -(1-28) was infused at 200 ng/min to steady-state conditions in chronically instrumented one-kidney conscious dogs . Clearances were measured in dogs with a normally filtering kidney and they were also measured after the glomerular filtration rate ( Q92565 ) was reduced to close to zero by acutely inflating a cuff around the renal artery ( P31749 ) , which resulted in minimal urine production and renal blood flow reduction to 59 % of the resting level . In normal dogs , P08235 was 1,090 +/- 134 ml/min with renal clearance rate ( RCR ) contributing only 13.9 % . After P31749 , P08235 fell to 864 +/- 151 ml/min , due in part to a fall in RCR ( -41.5 +/- 12.9 ml/min ) , but mostly due to a fall in " rest of the body " ( total renal ) clearance of P01160 . The reduced Q92565 accounted for virtually all the fall in RCR . Normal plasma P01160 half-life was 59.6 +/- 7.9 s . In conclusion , P08235 of P01160 was very high , approaching the cardiac output , suggesting that most of P01160 is cleared in one circulation through peripheral tissues . Q92565 contributed significantly to RCR ( approximately 30 % ) but the contribution of the kidney to whole body P08235 was small relative to rest of the body clearance of P01160 . Epidermal growth factor enhances androgen receptor‑mediated bladder cancer progression and invasion via potentiation of AR transactivation . P10275 ( AR ) plays a critical role in bladder cancer ( BCa ) development . Our early studies found AR knock-out mice ( with few androgens and deleted AR ) failed to develop BCa , yet 50 % of castrated mice ( with few androgens and existing AR ) still developed BCa in an N-butyl-N-(4-hydroxybutyl)nitrosamine ( BBN ) carcinogen-induced BCa mouse model , suggesting the existing AR in BCa of castrated mice may still play important roles in promoting BCa development at the castration level of androgens . The mechanism underlying this and/or which factors potentiate AR function at the castration level of androgen remains unclear . Epidermal growth factor ( P01133 ) , a key player in BCa progression , has been demonstrated to be able to potentiate AR transactivation in prostate cancer . In the present study , we found that P01133 could increase BCa cell growth , migration and invasion in the presence of AR under the low amount of androgen and P01133 was able to potentiate AR transactivation through P00533 by activating PI3K/AKT and MAPK pathway at castration androgen level . The increased suppression effects by P00533 inhibitor of PD168393 on AR function after addition of anti-androgen , DB01128 , further suggested AR might play a key role in the effects of P01133 on BCa progression and metastasis . Collectively , our results indicate that P01133 may be able to potentiate AR transactivation that leads to enhancing BCa progression , which may help us to develop a better therapeutic approach to treat BCa via targeting both P01133 and AR signaling . MYC directs transcription of Q07820 and P06730 genes to control sensitivity of gastric cancer cells toward HDAC inhibitors . Histone deacetylases ( HDACs ) control fundamental physiological processes such as proliferation and differentiation . HDAC inhibitors ( HDACi ) induce cell cycle arrest and apoptosis of tumor cells . Therefore , they represent promising cancer therapeutics that appear particularly useful in combination therapies . Although HDACi are tested in current clinical trials , the molecular mechanisms modulating the cellular responses toward HDACi are incompletely understood . To gain insight into pathways that limit HDACi efficacy in gastric cancer , we treated a panel of gastric cancer cells with the clinically relevant HDACi suberoylanilide hydroxamic acid ( DB02546 ) . We report that higher expression levels of the anti-apoptotic P10415 family members Q07820 and BCL(XL) were detectable in cells with high inhibitory concentration 50 ( IC(50) ) values for DB02546 . Using RNAi , we show that Q07820 and BCL(XL) lower the efficacy of DB02546 . To find strategies to interfere with Q07820 and BCL(XL) expression , we investigated molecular regulation of both proteins . We show that specific siRNAs against c-MYC as well as pharmacological inhibition of this cancer-relevant transcription factor reduced Q07820 and BCL(XL) expression . Subsequently , we observed an increase in DB02546 efficacy . Our data furthermore demonstrate that two different molecular mechanisms are responsible for the modulation of these factors . Whereas c-MYC controls transcription of Q07820 directly , regulation of BCL(XL) was due to c-MYC 's capability to regulate the P06730 gene , which encodes a rate-limiting factor of eukaryotic translation . Our data reveal a new molecular mechanism for how c-MYC controls cell autonomous apoptosis and provide a rationale for a concerted inhibition of HDACs and c-MYC in gastric cancer . Expression of P10721 and P09619 is associated with a good prognosis in neuroblastoma . BACKGROUND : The clinical outcome of neuroblastoma ( NB ) depends on age , stage , and P04198 amplification . Receptor tyrosine kinases ( RTKs ) promote cell growth , migration , and metastasis in cancer cells , including NB . However , the correlation of the expression profile of RTKs with prognosis in NB remains controversial . PROCEDURE : Expression and mutation analysis of P10721 , P09619 , P36888 , P07949 , and P04629 mRNAs were performed in 24 NB cell lines and 40 tumor samples using RT-PCR followed by direct sequencing . Immunohistochemical analysis of P10721 and P09619 protein expression was also examined in 38 paraffin sections of NB tumor samples . RESULTS : The expression of P10721 , PDGFRbeta , and P36888 mRNA was associated with NB in patients under 1 year ( P < 0.02 ) and P04629 expression ( P < 0.001 ) . The loss of expression of these kinases was associated with P04198 amplification ( P < 0.02 ) and advanced stages of disease in patients over 1 year of age ( P < 0.005 ) . PDGFRalpha mRNA expression was detected in all cell lines and tumor samples , and P07949 mRNA expression was not associated with any clinical parameters . Immunohistochemistry results showed the similar findings . We did not find any activating mutations in P10721 , P09619 , P36888 , or P07949 . Notably , the GNNK(-) isoform of P10721 was predominant in all cell lines and clinical samples . CONCLUSION : Expression of P10721 , PDGFRbeta , and P36888 was associated with a good prognosis in NB . The loss of expression of these RTKs might correlate to the disease progression of NB .