interacts_with DB00864?
Vampire bat plasminogen activator DB04925 -alpha-1 ( desmoteplase ) : a thrombolytic drug optimized by natural selection . P00747 activators are enzymes found in all vertebrate species investigated so far . Their physiological function is the generation of localized proteolysis in the context of tissue remodeling , wound healing and neuronal plasticity . The common vampire bat ( Desmodus rotundus ) is a New World species that feeds exclusively on blood . Its saliva contains highly potent plasminogen activators , specialized in rapid lysis of fresh blood clots . Biochemical and pharmacological evidence indicates that these plasminogen activators represent a new class of thrombolytics with pharmacological and toxicological properties superior to human tissue-type plasminogen activator , the clot dissolving agent now most frequently used in medicine . A form of the enzyme produced by recombinant DNA technology is currently employed to test this hypothesis in clinical studies . Q07973 as a potential target for cancer therapy . Increasing evidence has accumulated to suggest that vitamin D may reduce the risk of cancer through its biologically active metabolite , DB00136 , which inhibits proliferation and angiogenesis , induces differentiation and apoptosis , and regulates many other cellular functions . Thus , it is plausible to assume that rapid clearance of DB00136 by highly expressed Q07973 could interrupt the normal physiology of cells and might be one cause of cancer initiation and progression . In fact , enhancement of Q07973 expression has been reported in literature for many cancers . Based on these findings , Q07973 -specific inhibitors and vitamin D analogs which are resistant to Q07973 -dependent catabolism might be useful for cancer treatment . Q07973 -specific inhibitor VID400 , which is an azole compound , markedly enhanced and prolonged the antiproliferative activity of DB00136 in the human keratinocytes . Likewise , Q07973 -resistant analogs such as 2α-(3-hydroxypropoxy)- DB00136 ( O2C3 ) and its P06681 -epimer ED-71 ( DB05295 ) , and 19nor- 2α-(3-hydroxypropyl)- DB00136 ( MART-10 ) showed potent biological effects . Our in vivo studies using rats revealed that MART-10 had a low calcemic effect , which is a suitable property as an anticancer drug . Much lower affinity of MART-10 for vitamin D binding protein ( DBP ) as compared with DB00136 may be related to its more potent cellular activities . Based on these results , we conclude that ( 1 ) high affinity for P11473 , ( 2 ) resistance to Q07973 -dependent catabolism , ( 3 ) low affinity for DBP , and ( 4 ) low calcemic effect may be required for designing potent vitamin D analogs for cancer treatment . Biological profile of oestrogen receptor positive primary breast cancers in the elderly and response to primary endocrine therapy . P11511 inhibitors have been shown to be superior to Tamoxifen in several settings . It is unclear whether this superiority extends to their use as primary endocrine therapy in elderly patients with early operable primary breast cancer . Biological characteristics of the tumours may aid in selecting the most suitable agent . Primary endocrine therapy with DB01217 in 64 women > 70 years with oestrogen receptor alpha-positive ( ERalpha+ ) breast cancer was compared to that in 84 treated with Tamoxifen during the same period . Biomarkers were assessed by immunohistochemistry on diagnostic core biopsies . There was no significant difference between the two groups ( DB01217 vs Tamoxifen ) in terms of clinical benefit rates at 6 months ( 97 % vs 100 % ) or median progression free survival ( 16.5 vs 22.5 months ) . There were no withdrawals due to adverse events from DB01217 , compared to four with Tamoxifen . 46 % , 99 % , 8 % and 5 % of all patients were positive for progesterone receptor , ERbeta2 , P04626 and P00533 , respectively , and 64 % of patients had a moderate Ki-67 index . Positive P04626 status ( 18 vs 21 months , p=0.003 ) and moderate Ki-67 index ( 17.5 vs 23 months , p=0.042 ) were associated with significantly shorter progression free survival . Results thus far show that primary endocrine therapy with DB01217 in elderly patients with early operable ERalpha+ breast cancer is similar to Tamoxifen in terms of efficacy , but appears to be associated with less adverse events leading to withdrawals . In this population , ERalpha+ breast cancer also appears to have a less aggressive biological profile favouring better hormone sensitivity . Cytokine induced changes in proteasome subunit composition are concentration dependent . In eukaryotes , 20S proteasome subunit composition is controlled by the cytokine interferon-gamma ( P01579 ) . P01579 induces the synthesis of the beta-subunits P28065 , P28062 and MECL-1 , which in consequence replace their constitutive subunit homologs delta , MB1 and MC14/Z in the 20S complex . By pulse labeling mouse RMA cells and immunoprecipitation of proteasome complexes with the antibody MP3 , we have analysed the effect of different P01579 concentrations on proteasomal subunit composition . Our experiments show that P01579 concentrations as low as 5 U/ml induce subunit substitutions and that overall proteasomal subunit composition is dependent on the cytokine concentration used . An P01579 concentration of 50 U/ml is sufficient for complete replacement of subunit delta by P28065 . In contrast , P01579 treatment never induces a complete replacement of subunit MC14 by MECL-1 . These subunits are present at an approximate 1:1 molar ratio , suggesting that both subunits coexist in the same 20S proteasome complex . Furthermore , different regulatory mechanisms have to be postulated for the synthesis and incorporation of the three P01579 inducible proteasome subunits . Both P01579 as well as P60568 also seem to influence the modification state of the alpha subunit Q99618 . Since the subunit composition is dependent on the cytokine concentration used and strongly influences the proteolytic properties of the 20S proteasome complex , our experiments represent a caveat for experiments in which P01579 dependent proteasomal enzyme characteristics have been analysed without monitoring the subunit composition . Selective peroxisome proliferator-activated receptor α modulators ( SPPARMα ) : the next generation of peroxisome proliferator-activated receptor α-agonists . Dyslipidemia is a major risk factor for cardiovascular ( CV ) disease - the primary cause of death , worldwide . Although reducing levels of low-density lipoprotein-cholesterol can significantly reduce CV risk , a high level of residual risk persists , especially in people with obesity-related conditions , such as metabolic syndrome and type 2 diabetes mellitus . Q07869 - ( PPARα- ) agonists ( e.g. fibrates ) , play a central role in the reduction of macro- and microvascular risk in these patients . However , the currently available fibrates are weak ( PPARα-agonists ) with limited efficacy due to dose-related adverse effects . To address this problem , a new generation of highly potent and selective PPARα-modulators ( SPPARMα ) is being developed that separate the benefits of the PPARα-agonists from their unwanted side effects . Among these , aleglitazar ( a dual PPARα/γ agonist ) and DB05187 ( a dual Q07869 α/δ agonist ) have recently entered late-phase development . Although both compounds are more potent PPARα-activators than fenofibrate in vitro , only aleglitezar is more effective in lowering triglycerides and raising high-density lipoprotein-cholesterol ( HDL-C ) in humans . However , it is also associated with a potential risk of adverse effects . More recently , a highly potent , specific PPARα-agonist ( K-877 ) has emerged with SPPARMα characteristics . Compared to fenofibrate , K-877 has more potent PPARα-activating efficacy in vitro , greater effects on triglycerides- and HDL-C levels in humans , and a reduced risk of adverse effects . If successful , K-877 has the potential to supersede the fibrates as the treatment of choice for patients with residual CV risk associated with metabolic syndrome and type 2 diabetes . Cloning of a novel phosphatidylinositol kinase-related kinase : characterization of the human Q96Q15 RNA surveillance protein . We have cloned and characterized a new member of the phosphatidylinositol kinase ( PIK ) -related kinase family . This gene , which we term human Q96Q15 ( Q96Q15 ) , is orthologous to Caenorhabditis elegans Q96Q15 , a protein that functions in nonsense-mediated mRNA decay ( Q53H76 ). cDNA sequencing revealed that Q96Q15 encodes a protein of 3031 amino acids containing a conserved kinase domain , a C-terminal domain unique to the PIK-related kinases and an P62942 -rapamycin binding-like domain similar to that found in the PIK-related kinase P42345 . Immunopurified FLAG-tagged Q96Q15 exhibits protein kinase activity as measured by autophosphorylation and phosphorylation of the generic PIK-related kinase substrate PHAS-1. Q96Q15 kinase activity is inhibited by high nanomolar concentrations of wortmannin ( IC(50) = 105 nm ) but is not inhibited by a P62942 -rapamycin complex . Mutation of conserved residues within the kinase domain of Q96Q15 abolishes both autophosphorylation and substrate phosphorylation , demonstrating that Q96Q15 exhibits intrinsic protein kinase activity . Q96Q15 phosphorylates purified Q92900 protein , a phosphoprotein that plays a critical role in Q53H76 , at sites that are also phosphorylated in whole cells . Based on these data , we conclude that Q96Q15 is the human orthologue to C. elegans Q96Q15 . Our data indicate that Q96Q15 may function in Q53H76 by directly phosphorylating Q92900 protein at physiologically relevant sites . Immunization strategies to augment oral vaccination with DNA and viral vectors expressing HIV envelope glycoprotein . Induction of mucosal immunity to the human immunodeficiency virus ( HIV ) envelope ( env ; gp160 ) glycoprotein has been demonstrated with orally administered recombinant vaccinia virus ( rVV ) vectors and poly(DL-lactide-co-glycolide) ( P00747 ) -encapsulated plasmid DNA expressing gp160 . In this study , we investigated the effect of an oral DNA-prime/rVV-boost vaccine regimen in conjunction with adjuvants on the level of gp160-specific cellular and humoral responses in BALB/c mice . We demonstrated that DNA priming followed by a booster with rVV expressing gp160 ( vPE16 ) significantly augmented env-specific immunity in systemic and mucosal tissues of the immunized mice . Association of vPE16 with liposomes and coadministration of liposome-associated beta-glucan lentinan or P60568 /Ig-encoded plasmid DNA-encapsulated in P00747 microparticles triggered the optimal cell-mediated immune ( CMI ) responses . Lentinan was found to increase env-specific type 1 cytokine production and cytotoxic T-lymphocyte ( CTL ) activities but had no effect on humoral responses . On the other hand , P60568 /Ig-mediated increases in both type 1 and 2 activities were associated with higher levels of env-specific CTL and antibody responses . Results of these studies demonstrated the effectiveness of oral vaccines with DNA and rVV vectors in conjunction with immunomodulators in inducing specific immune responses in systemic and mucosal tissues . [ Proteolytic processing by dipeptidyl aminopeptidase IV generates receptor selectivity for peptide YY ( P10082 ) ] . Two receptor subtypes , Q03519 and P28062 , are known to mediate P10082 biological activity . P10082 1-36 binds to Q03519 and P28062 receptors with equal affinity , whereas the second endogenous form of P10082 , DB05004 , selectively binds to P28062 receptors . Dipeptidyl cleavage thus transforms an unselective Y agonist into a highly selective P28062 agonist , DB05004 . The enzyme responsible for this processing is unknown . Since P10082 has a proline in the penultimate position it is protected from the attack of most unspecific exopeptidases . Only a few exopeptidases are theoretically capable of generating DB05004 from P10082 1-36 . Of the enzymes tested only the dipeptidyl aminopeptidase IV ( P27487 , E.C. 3.4.14.5 ) cleaved DB00135 -Pro from P10082 1-36 with high activity . Since P27487 is found on the endothelial surface and brush border membranes it can be considered a candidate enzyme for generating DB05004 in vivo , thereby regulating the ratio of Q03519 / P49146 stimulation by P10082 . DB00877 induces the TGFbeta1/Smad signaling cascade in renal mesangial cells upstream of P42345 . The P42345 kinase inhibitor rapamycin ( sirolimus ) is a drug with potent immunosuppressive and antiproliferative properties . We found that rapamycin induces the TGFbeta/Smad signaling cascade in rat mesangial cells ( MC ) as depicted by the nuclear translocation of phospho-Smads 2 , -3 and Smad-4 , respectively . Concomitantly , rapamycin increases the nuclear DNA binding of receptor ( R ) - and co-Smad proteins to a cognate Smad-binding element ( SBE ) which in turn causes an increase in profibrotic gene expression as exemplified by the connective tissue growth factor ( P29279 ) and plasminogen activator inhibitor 1 ( P05121 ) . Using small interfering (si)RNA we demonstrate that Smad 2/3 activation by rapamycin depends on its endogenous receptor FK binding protein 12 ( P62942 ) . Mechanistically , Smad induction by rapamycin is initiated by an increase in active TGFbeta(1) as shown by ELISA and by the inhibitory effects of a neutralizing TGFbeta antibody . Using an activin receptor-like kinase ( Q9UM73 ) -5 inhibitor and by siRNA against the TGFbeta type II receptor ( TGFbeta-RII ) we furthermore demonstrate a functional involvement of both types of TGFbeta receptors . However , rapamycin did not compete with TGFbeta for TGFbeta-receptor binding as found in radioligand-binding assay . Besides SB203580 , a specific inhibitor of the p38 MAPK , the reactive oxygen species ( ROS ) scavenger N-acetyl-cysteine ( Q9C000 ) and a cell-permeable superoxide dismutase ( SOD ) mimetic strongly abrogated the stimulatory effects of rapamycin on Smad 2 and 3 phosphorylation . Furthermore , the rapid increase in dichlorofluorescein ( DCF ) formation implies that rapamycin mainly acts through ROS . In conclusion , activation of the profibrotic TGFbeta/Smad signaling cascade accompanies the immunosuppressive and antiproliferative actions of rapamycin . 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 . Q9GZP0 inhibition by DB05139 ameliorates tubulointerstitial fibrosis following experimental glomerulonephritis . BACKGROUND : Arresting or regressing kidney scarring is of major clinical relevance . Q9GZP0 ( Q9GZP0 ) is widely expressed in fibrotic kidneys . Administration of the Q9GZP0 neutralizing fully human monoclonal antibody DB05139 in the acute phase of progressive anti-Thy 1.1 glomerulonephritis reduced glomerular and secondary tubulointerstitial damage . METHODS : Using this model , we now assessed the effects of DB05139 ( n=15 ) vs irrelevant control IgG ( n=17 ) administered on days 17 , 28 and 35 after disease induction , i.e. after acute glomerular damage had subsided . RESULTS : In vitro , DB05139 inhibited the Q9GZP0 - but not the PDGF-B-induced proliferation of rat renal fibroblasts . Following the first DB05139 injection on day 17 , exposure to therapeutic levels was maintained until day 49 . Proteinuria in the DB05139 -treated group was transiently reduced between days 49 and 77 ( -19 to -23 % in comparison with the controls ; P < 0.05 ) . On day 100 , DB05139 treatment reduced the number of rats that had doubled their serum creatinine ( DB05139 : 40 vs controls : 71 % ; P < 0.05 ) . Compared with controls , the DB05139 animals , on day 100 , significantly lowered glomerular expression of vimentin and collagens as well as tubulointerstitial damage scores , interstitial fibrosis , vimentin and cortical Q9GZP0 mRNA levels . CONCLUSIONS : Q9GZP0 antagonism , even after the phase of acute glomerular damage , exerts beneficial effects on the course of tubulointerstitial damage , i.e. the final common pathway of most renal diseases . Selective antitumor activity of ibrutinib in P00533 -mutant non-small cell lung cancer cells . DB09053 , which irreversibly inhibits Q06187 , was evaluated for antitumor activity in a panel of non-small cell lung cancer ( NSCLC ) cell lines and found to selectively inhibit growth of NSCLC cells carrying mutations in the epidermal growth factor receptor ( P00533 ) gene , including T790M mutant and erlotinib-resistant H1975 cells . DB09053 induced dose-dependent inhibition of phosphor- P00533 at both Y1068 and Y1173 sites , suggesting ibrutinib functions as an P00533 inhibitor . Survival was analyzed by Kaplan-Meier estimation and log-rank test . All statistical tests were two-sided . In vivo study showed that ibrutinib statistically significantly suppressed H1975 tumor growth and prolonged survival of the tumor bearing mice ( n = 5 per group ) . The mean survival times for solvent- and erlotinib-treated mice were both 17.8 days ( 95 % confidence interval [ CI ] = 14.3 to 21.3 days ) , while the mean survival time for ibrutinib-treated mice was 29.8 days ( 95 % CI = 26.0 to 33.6 days , P = .008 ) . Our results indicate that ibrutinib could be a candidate drug for treatment of P00533 -mutant NSCLC , including erlotinib-resistant tumors . A P43220 agonist liraglutide inhibits endothelial cell dysfunction and vascular adhesion molecule expression in an ApoE-/- mouse model . The glucagon like peptide-1 receptor ( P43220 ) agonist liraglutide attenuates induction of plasminogen activator inhibitor type-1 ( P05121 ) and vascular adhesion molecule ( VAM ) expression in human vascular endothelial cells ( hVECs ) in vitro and may afford protection against endothelial cell dysfunction ( O95905 ) , an early abnormality in diabetic vascular disease . Our study aimed to establish the dependence of the in vitro effects of liraglutide on the P43220 and characterise its in vivo effects in a mouse model of O95905 . In vitro studies utilised the human vascular endothelial cell line P10144 - Q8IWL8 and enzyme-linked immunosorbent assays ( ELISA ) for determination of P05121 and VAM expression . In vivo studies of vascular reactivity and immunohistochemical analysis were performed in the ApoE(-/-) mouse model . In vitro studies demonstrated P43220 -dependent liraglutide-mediated inhibition of stimulated P05121 and VAM expression . In vivo studies demonstrated significant improvement in endothelial function in liraglutide treated mice , a P43220 dependent effect . DB06655 treatment also increased endothelial nitric oxide synthase ( P29474 ) and reduced intercellular adhesion molecule-1 ( P05362 ) expression in aortic endothelium , an effect again dependent on the P43220 . Together these studies identify in vivo protection , by the P43220 agonist liraglutide , against O95905 and provide a potential molecular mechanism responsible for these effects . 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 . P42345 repression by 3,3'-diindolylmethane inhibits invasion and angiogenesis in platelet-derived growth factor-D-overexpressing PC3 cells . Platelet-derived growth factor-D ( Q9GZP0 ) is a newly recognized growth factor known to regulate many cellular processes , including cell proliferation , transformation , invasion , and angiogenesis . Recent studies have shown that Q9GZP0 and its cognate receptor P09619 are expressed in prostate tumor tissues , suggesting that Q9GZP0 might play an important role in the development and progression of prostate cancer . However , the biological role of Q9GZP0 in tumorigenesis remains elusive . In this study , we found that Q9GZP0 -overexpressing PC3 cells ( PC3 cells stably transfected with Q9GZP0 cDNA and referred to as PC3 Q9GZP0 ) exhibited a rapid growth rate and enhanced cell invasion that was associated with the activation of mammalian target of rapamycin ( P42345 ) and reduced Akt activity . DB00877 repressed P42345 activity and concomitantly resulted in the activation of Akt , which could attenuate the therapeutic effects of P42345 inhibitors . In contrast , B-DIM ( BR-DIM from Bioresponse , Inc. ; a chemopreventive agent ) significantly inhibited both P42345 and Akt in PC3 Q9GZP0 cells , which were correlated with decreased cell proliferation and invasion . Moreover , conditioned medium from PC3 Q9GZP0 cells significantly increased the tube formation of human umbilical vein endothelial cells , which was inhibited by B-DIM treatment concomitant with reduced full-length and active form of Q9GZP0 . Our results suggest that B-DIM could serve as a novel and efficient chemopreventive and/or therapeutic agent by inactivation of both P42345 and Akt activity in Q9GZP0 -overexpressing prostate cancer . A transcriptional block in the P60568 promoter at the -150 AP-1 site in effector CD8+ T cells . Both P01730 + and CD8+ T cells that produce P60568 in response to Ag recognition have been isolated . However , most effector CD8+ T cells recovered after exposure to Ag do not produce sufficient P60568 to sustain growth , and depend on P01730 + T helper cells for this obligate growth factor . P60568 expression in P01730 + T cells is primarily controlled at the level of transcription , but mechanisms restricting P60568 production in CD8+ T cells have not been elucidated . To evaluate transcriptional regulation of the P60568 gene in CD8+ T cells , we stably transfected reporter genes into Ag-specific CD8+ T cell clones . P10747 + CD8(+) T cells unable to transcribe the P60568 gene in response to antigenic stimulation had a block in transactivation of the -150 P10747 response element ( CD28RE ) /AP-1 site of the P60568 promoter , but did transactivate the composite NFAT/AP-1 and O75051 /AP-1 sites , and a consensus AP-1 motif . Mutation of the nonconsensus -150 AP-1 site to a consensus AP-1 site , or insertion of a CD28RE/AP-1 consensus site upstream of the native -150 CD28RE/AP-1 site restored transactivation of the altered promoter . These results suggest that the defect at the -150 site may reflect the absence or inactivity of a required factor rather than repression of the P60568 promoter . Vitamin D analogues . The plethora of actions attributed to 1,25(OH)2D3 throughout the body have suggested potential therapeutic applications for the treatment of hyperproliferative diseases , immune dysfunction , endocrine disorders , and metabolic bone disease . However , the potent calcemic activity of the natural vitamin D hormone has precluded its use in most cases . New vitamin D analogues are under development that display greater specificity , in most cases , by retaining the therapeutic properties of 1,25(OH)2D3 , but with lower calcemic activity . Two analogues have been approved for use in patients : calcipotriol ( DB02300 from Leo Pharmaceuticals , Copenhagen , Denmark ) for the treatment of psoriasis ; and 19-nor-1,25(OH)2D2 ( DB00910 from Abbott Laboratories , Abbott Park , IL ) for secondary hyperparathyroidism . Many others analogues are currently being tested in preclinical and clinical trials for the treatment of various types of cancer and osteoporosis , and for immunosuppression . The selectivity of the analogues can be attributed to the combined interactions with four proteins : the vitamin D receptor ( P11473 ) , the serum vitamin D binding protein ( DBP ) , the vitamin D-24-hydroxylase and to a newly described membrane receptor . Low DBP affinity has been shown to be responsible for the reduced calcemic actions of calcipotriol and 22-oxacalcitriol ( O75051 ) , which is being tested for secondary hyperparathyroidism . However , the low calcemic activity of other analogues , including 19-nor-1,25(OH)2D2 , involves other , as yet undefined , mechanisms . Understanding of the molecular basis for the selectivity of the vitamin D analogues will allow the design of more effective and safer vitamin D compounds for the treatment of a wide range of clinical disorders . Forced dimerization increases the activity of Δ P00533 /EGFRvIII and enhances its oncogenicity . Delta epidermal growth factor receptor ( Δ P00533 ) , an in-frame deletion mutant of the extracellular ligand-binding domain , which occurs in about 30 % of glioblastoma , is a potent oncogene that promotes tumor growth and progression . The signaling of Δ P00533 is ligand-independent and low intensity , allowing it to evade the normal mechanisms of internalization and degradation by the endocytic machinery and hence is persistent . The basis of the oncogenic potential of Δ P00533 remains incompletely understood , including whether dimerization plays an important role in its signal and whether its oncogenic potential is dependent on its relatively low intensity , when compared with the acutely activated wild-type receptor . To examine these two important questions , we have generated a chimeric Δ P00533 that allows forced dimerization via domains derived from variants of the P62942 protein that are brought together by FK506 derivatives . Forced dimerization of chimeric Δ P00533 significantly increased the intensity of its signal , as measured by receptor phosphorylation levels , suggesting that the naturally occurring Δ P00533 does not form strong or stable dimers as part of its low level signal . Interestingly , the increased activity of dimerized , chimeric Δ P00533 did not promote receptor internalization , implying that reduced rate of endocytic downregulation of Δ P00533 is an inherent characteristic . Significantly , forced dimerization enhanced the oncogenic signal of the receptor , implying that the Δ P00533 is a potent oncogene despite , not because of its low intensity . Anti-allergic function and regulatory mechanisms of KR62980 in allergen-induced airway inflammation . The ligand-activated transcription factor , peroxisome proliferator-activated receptor ( Q07869 )gamma , and its ligands inhibit pro-inflammatory cytokine production by immune cells , thus exerting anti-inflammatory activity . As a non-thiazolidinedione PPARgamma ligand , KR62980 has anti-diabetic and anti-adipogenic activities , but its anti-inflammatory function has yet to be characterized . In this study , we investigated the functions and mechanisms of KR62980 in the activation and differentiation of P01730 + T helper ( Th ) cells by comparing its effects with those of a thiazolidinedione PPARgamma ligand , rosiglitazone . KR62980 dose-dependently and significantly suppressed TCR-triggered Th cell proliferation by suppressing P60568 /IL-2Ralpha-mediated signaling . Both KR62980 and rosiglitazone suppressed IFNgamma production in a dose-dependent manner , whereas P05112 gene expression was specifically suppressed by only KR62980 . In addition , sustained KR62980 treatment diminished Th2 cytokine production by inhibiting c-Maf expression . In vivo administration of KR62980 in a model of allergic asthma significantly attenuated eotaxin-induced eosinophil infiltration , allergic cytokine production and collagen deposition in the lung . KR62980 also decreased goblet cell hyperplasia in the airway and mucous cell metaplasia in nasal epithelium , concurrent with decreases of allergic Th2 cytokines and Q16552 in the draining lymph node . In conclusion , a novel PPARgamma ligand , KR62980 , suppresses in vitro Th2 cell differentiation and attenuates in vivo OVA-induced airway inflammation , suggesting a beneficial role for KR62980 in the treatment of allergic asthma and allergic rhinitis . Calcineurin enhances acetylcholinesterase mRNA stability during P06681 -C12 muscle cell differentiation . Treatment of P06681 -C12 mouse myoblasts with the immunosuppressant drug cyclosporin A ( DB00091 ) enhances the increase in acetylcholinesterase ( P22303 ) expression observed during skeletal muscle differentiation . The enhanced P22303 expression is due primarily to increased mRNA stability because DB00091 treatment increases the half-life of P22303 mRNA , but not the apparent transcriptional rate of the gene . Neither tacrolimus ( FK506 ) , an immunosuppressive agent with a distinct structure , nor cyclosporine H , an inactive congener of DB00091 , alters P22303 expression . The enhanced P22303 expression is associated with the muscle differentiation process , but can not be triggered by DB00091 exposure before differentiation . Myoblasts and myotubes of P06681 -C12 cells express similar amounts of cyclophilin A and P62942 , immunophilins known to be intracellular-binding targets for DB00091 and tacrolimus , respectively . However , cellular levels of calcineurin , a calcium/calmodulin-dependent phosphatase known to be the cellular target of ligand-immunophilin complexes , increase 3-fold during myogenesis . Overexpression of constitutively active calcineurin in differentiating cells reduces P22303 mRNA levels and DB00091 antagonizes such an inhibition . Conversely , overexpression of a dominant negative calcineurin construct increases P22303 mRNA levels , which are further enhanced by DB00091 . Thus , a DB00091 sensitive , calcineurin mediated pathway appears linked to differentiation-induced stabilization of P22303 mRNA during myogenesis .