interacts_with DB01064?
A new role for the P40763 inhibitor , Q9Y6X2 : a repressor of microphthalmia transcription factor . In vitro and in vivo evidence suggest that microphthalmia transcription factor ( O75030 ) plays a key regulatory role in tissue-specific gene regulation in several cell types , including melanocytes , osteoclasts , and mast cells . A yeast two-hybrid search , using a portion of a nonmutated O75030 gene as the bait in the screening of a mast cell library , resulted in the isolation of the P40763 inhibitor , Q9Y6X2 . Q9Y6X2 is a transcriptional inhibitor that acts by specifically inhibiting P40763 's DNA binding activity . We found that it can directly associate with O75030 using an in vitro pull-down assay . Immunoprecipitation of O75030 from rat basophilic leukemic cells or mouse melanocytes resulted in the specific co-immunoprecipitation of Q9Y6X2 . Co-transfection of O75030 with Q9Y6X2 in NIH 3T3 fibroblasts containing an mMCP-6 promoter-luciferase reporter demonstrated up to 94 % inhibition of O75030 -mediated transcriptional activation . Using a gel-shift assay , it was shown that Q9Y6X2 can block DNA binding activity . It was also found that P40763 does not interfere , either in vitro or in vivo , with the interaction between Q9Y6X2 and O75030 . These data suggest that Q9Y6X2 functions in vivo as a key molecule in supressing the transcriptional activity of O75030 , a role of considerable importance in mast cell and melanocyte development . Opposing actions of extracellular signal-regulated kinase ( P29323 ) and signal transducer and activator of transcription 3 ( P40763 ) in regulating microtubule stabilization during cardiac hypertrophy . Excessive proliferation and stabilization of the microtubule ( MT ) array in cardiac myocytes can accompany pathological cardiac hypertrophy , but the molecular control of these changes remains poorly characterized . In this study , we examined MT stabilization in two independent murine models of heart failure and revealed increases in the levels of post-translationally modified stable MTs , which were closely associated with P40763 activation . To explore the molecular signaling events contributing to control of the cardiac MT network , we stimulated cardiac myocytes with an α-adrenergic agonist phenylephrine ( PE ) , and observed increased tubulin content without changes in detyrosinated ( glu-tubulin ) stable MTs . In contrast , the hypertrophic interleukin-6 ( P05231 ) family cytokines increased both the glu-tubulin content and glu-MT density . When we examined a role for P29323 in regulating cardiac MTs , we showed that the MEK/ P29323 -inhibitor U0126 increased glu-MT density in either control cardiac myocytes or following exposure to hypertrophic agents . Conversely , expression of an activated Q02750 mutant reduced glu-tubulin levels . Thus , P29323 signaling antagonizes stabilization of the cardiac MT array . In contrast , inhibiting either O60674 with AG490 , or P40763 signaling with Stattic or siRNA knockdown , blocked cytokine-stimulated increases in glu-MT density . Furthermore , the expression of a constitutively active P40763 mutant triggered increased glu-MT density in the absence of hypertrophic stimulation . Thus , P40763 activation contributes substantially to cytokine-stimulated glu-MT changes . Taken together , our results highlight the opposing actions of P40763 and P29323 pathways in the regulation of MT changes associated with cardiac myocyte hypertrophy . Prasugrel : a new antiplatelet drug for the prevention and treatment of cardiovascular disease . Prasugrel , trade name DB06209 , is an investigational new antiplatelet drug currently under review for clinical use by the Food and Drug Administration . It is a thienopyridine analog with a structure similar to that of clopidogrel and ticlopidine . Thienopyridine derivatives inhibit platelet aggregation induced by adenosine diphosphate by irreversibly inhibiting the binding of adenosine diphosphate to the purinergic Q9H244 receptor on the platelet surface . Prasugrel has been shown to be a potent antiplatelet agent with a faster , more consistent , and greater inhibition of platelet aggregation compared with clopidogrel . It is debatable , however , how effectively these pharmacologic benefits will translate to clinical benefits . The results of the large TRITON-TIMI 38 trial , which compared prasugrel and clopidogrel in patients with acute coronary syndrome who were scheduled to receive coronary stents , demonstrated a significant reduction in ischemic events , including stent thrombosis , with prasugrel , but with an increased risk of major bleeding . The exact role of prasugrel in the management of ischemic heart disease is still being defined , but the risk:benefit ratio will likely play a major role in directing the best place for therapy with this new agent . DB00909 block of cloned human T-type voltage-gated calcium channels . DB00909 ( ZNS ) is a multi-target antiepileptic drug reported to be efficient in the treatment of both partial and generalized seizures , with T-type Ca(2+) channel blockade being one of its proposed mechanisms of action . In this study , we systematically investigated electrophysiological effects of ZNS on cloned human Ca(v)3.1-3.3 Ca(2+) channels in a heterologous P29320 -293 expression system using whole cell patch-clamp technique . Concentration-response studies were performed in the range from 5 microM to 2mM for Ca(v)3.2 Ca(2+) channels exhibiting a 15.4-30.8 % reduction of Ca(2+) influx within the maximum therapeutic plasma range ( 50-200 microM ZNS ) . The other T-type Ca(2+) channel entities , Ca(v)3.1 and Q9P0X4 , were even less sensitive to ZNS . Both voltage- and concentration-dependence of inactivation kinetics remained unchanged for Ca(v)3.2 VGCC , whereas Ca(v)3.1 and Q9P0X4 exhibited minor , though significant reduction of inactivation-tau . Interestingly , ZNS block of Ca(v)3.2 VGCCs was not use-dependent and remained unaffected by changes in the holding potential . Steady-state inactivation studies did not display a significant shift in steady-state availability of Ca(v)3.2 channels at 100 microM ZNS ( DeltaV(1/2)=3.1mV , p=0.071 ) . Our studies indicate that ZNS is a moderate blocker of human Ca(v)3 T-type Ca(2+) channels with little or no effect on Ca(v)3.2 Ca(2+) channel inactivation kinetics , use- and state-dependence of blockade . These results suggest that T-type Ca(2+) channel inhibition only partially contributes to the anti-absence activity of ZNS antiepileptic drug . Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen DB00977 ( EE ) and bisphenol-A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( DB00603 ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER-labelled neurons were higher in males than in females in the ARC and DB00603 . EE and Q03001 increased ER-labelled neurons in the ARC and DB00603 . At P01160 90 , females showed higher ER-labelled neurons in the VMH . EE and Q03001 increased ER-labelled neurons in the DB00603 in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats . DB01095 inhibits growth and alters the malignant phenotype of the P13671 glioma cell line . BACKGROUND : DB01095 is a member of the family of P04035 inhibitors ( statins ) extensively used in medical practice . Increasing evidence suggests that fluvastatin may be implicated in suppression of cancer growth and development . The aim of the present study was to investigate the anti-cancer potential of fluvastatin in P13671 rat malignant glioma cells . METHODS : First , the effects of fluvastatin on cell viability ( MTT assay ) , proliferation ( BrdU assay ) , cell morphology , and cytoskeleton were examined . Subsequently , its effect on extracellular signal regulated kinase 1 and 2 ( P27361 /2 ) and P45983 and 2 ( JNK 1/2 ) expression was estimated by Western blot . Finally , the influence of fluvastatin on cell migration and production of P14780 and P15692 was determined using a wound-healing assay and ELISA test , respectively . RESULTS : The results obtained showed that fluvastatin had a remarkable inhibitory and cytotoxic effect on tumor P13671 cells ( IC(50) = 8.6 μM , 48 h ) , but did not inhibit the growth of normal neuronal cells . The concentrations from 1 to 10 μM induced marked morphologic alterations typical for apoptosis including shrinkage of cytoplasm , chromatin condensation , and nucleus breakdown . CONCLUSION : The inhibitory effects of fluvastatin on cell proliferation seemed to be associated with decreased p- P27361 /2 expression , upregulation of p- P45983 /2 , and reduction in the P14780 and P15692 concentrations in culture media . The high anticancer ( antiproliferative , proapoptotic , antiinvasive ) activity of fluvastatin and lack of its toxicity against normal cells indicate a potential use of this statin in the treatment of malignant glioma . Activation of c-Jun-N-terminal-kinase is crucial for the induction of a cell cycle arrest in human colon carcinoma cells caused by flurbiprofen enantiomers . The unselective cyclooxygenase ( P36551 ) inhibitor DB00712 and its-in terms of P36551 -inhibition- " inactive " enantiomer R-flurbiprofen have been previously found to inhibit tumor development and growth in various animal models . The underlying mechanisms are unknown . Here , we show that both R- and DB00712 reduce survival of three colon cancer cell lines , which differ in the expression of P35354 ( HCT-15 , no P35354 ; Caco-2 , inducible P35354 ; and HT-29 , constitutive P35354 ) . The IC50 for S- and R-flurbiprofen ranged from 250 to 450 microM . Both flurbiprofen enantiomers induced apoptosis in all three cell lines as indicated by DNA- and PARP-cleavage . In addition , R- and DB00712 caused a P55008 -cell cycle block . The latter was associated with an activation of c-Jun N-terminal kinase ( JNK ) , an increase of the DNA binding activity of the transcription factor AP-1 and down-regulation of cyclin D1 expression . Western blot analysis , as well as supershift experiments , revealed that the AP-1 activation was associated with a change of AP-1 composition toward an increase of JunB . The JNK inhibitor SP600125 antagonized R- and DB00712 -induced AP-1 DNA binding , suppression of cyclin D1 expression , and the P55008 -cell cycle block . However , JNK inhibition had no effect on flurbiprofen-induced apoptosis . Hence , the cell cycle arrest is obviously mediated , at least in part , through JNK-activation , whereas R- and DB00712 -induced apoptosis is largely independent of JNK . Although in vitro effects of R- and DB00712 were indistinguishable , only R-flurbiprofen inhibited HCT-15 tumor growth in nude mice , suggesting the involvement of additional in vivo targets , which are differently affected by R- and DB00712 . The expression level of P21554 and CB2 receptors determines their efficacy at inducing apoptosis in astrocytomas . BACKGROUND : Cannabinoids represent unique compounds for treating tumors , including astrocytomas . Whether CB(1) and CB(2) receptors mediate this therapeutic effect is unclear . PRINCIPAL FINDINGS : We generated astrocytoma subclones that express set levels of CB(1) and CB(2) , and found that cannabinoids induce apoptosis only in cells expressing low levels of receptors that couple to P27361 /2 . In contrast , cannabinoids do not induce apoptosis in cells expressing high levels of receptors because these now also couple to the prosurvival signal AKT . Remarkably , cannabinoids applied at high concentration induce apoptosis in all subclones independently of CB(1) , CB(2) and AKT , but still through a mechanism involving P27361 /2 . SIGNIFICANCE : The high expression level of CB(1) and CB(2) receptors commonly found in malignant astrocytomas precludes the use of cannabinoids as therapeutics , unless AKT is concomitantly inhibited , or cannabinoids are applied at concentrations that bypass CB(1) and CB(2) receptors , yet still activate P27361 /2 . Regulation and functional consequences of ADP receptor-mediated P28482 activation in platelets . We have previously shown that ADP-induced thromboxane generation in platelets requires signalling events from the G(q)-coupled P47900 receptor ( platelet ADP receptor coupled to stimulation of phospholipase C ) and the G(i)-coupled Q9H244 receptor ( platelet ADP receptor coupled to inhibition of adenylate cyclase ) in addition to outside-in signalling . While it is also known that extracellular calcium negatively regulates ADP-induced thromboxane A2 generation , the underlying mechanism remains unclear . In the present study we sought to elucidate the signalling mechanisms and regulation by extracellular calcium of ADP-induced thromboxane A2 generation in platelets . P29323 ( extracllular-signal-regulated kinase ) 2 activation occurred when outside-in signalling was blocked , indicating that it is a downstream event from the P2Y receptors . However , blockade of either P47900 or the Q9H244 receptors with corresponding antagonists completely abolished P29323 phosphorylation , indicating that both P2Y receptors are required for ADP-induced P29323 activation . Inhibitors of Src family kinases or the P29323 upstream kinase MEK [ MAPK ( mitogen-activated protein kinase ) / P29323 kinase ] abrogated ADP-induced P29323 phosphorylation and thromboxane A2 generation . Finally ADP- or G(i)+G(z)-induced P29323 phosphorylation was blocked in the presence of extracellular calcium . The present studies show that P28482 is activated downstream of P2Y receptors through a complex mechanism involving Src kinases and this plays an important role in ADP-induced thromboxane A2 generation . We also conclude that extracellular calcium blocks ADP-induced thromboxane A2 generation through the inhibition of P29323 activation . Q9H4A3 activates large-conductance Ca2+-activated K+ channels through modulation of P27361 /2 signaling . With no lysine ( WNK ) kinases are members of the serine/threonine kinase family . We previously showed that Q96J92 inhibits renal large-conductance Ca(2+)-activated K(+) ( BK ) channel activity by enhancing its degradation through a lysosomal pathway . In this study , we investigated the effect of Q9H4A3 on Q12791 activity . In HEK293 cells stably expressing the α subunit of BK ( P29320 -BKα cells ) , siRNA-mediated knockdown of Q9H4A3 expression significantly inhibited both BKα channel activity and open probability . Knockdown of Q9H4A3 expression also significantly inhibited BKα protein expression and increased P27361 /2 phosphorylation , whereas overexpression of Q9H4A3 significantly enhanced BKα expression and decreased P27361 /2 phosphorylation in a dose-dependent manner in HEK293 cells . Knockdown of P27361 /2 prevented Q9H4A3 siRNA-mediated inhibition of BKα expression . Similarly , pretreatment of P29320 -BKα cells with the lysosomal inhibitor bafilomycin A1 reversed the inhibitory effects of Q9H4A3 siRNA on BKα expression in a dose-dependent manner . Knockdown of Q9H4A3 expression also increased the ubiquitination of BKα channels . Notably , mice fed a high-K(+) diet for 10 days had significantly higher renal protein expression levels of BKα and Q9H4A3 and lower levels of P27361 /2 phosphorylation compared with mice fed a normal-K(+) diet . These data suggest that Q9H4A3 enhances Q12791 function by reducing P27361 /2 signaling-mediated lysosomal degradation of the channel . DB01064 inhibits fibroblast growth factor-2-induced growth of renal epithelial cells . The signal transduction pathways modulating P09038 effects in renal tubular epithelial cells ( RTEc ) are not completely understood . Since the DB02527 and the mitogen-activated protein kinase ( MAPK ) pathways can modulate the growth of RTEc , we studied whether two DB02527 elevating agents , isoproterenol and 8-bromo- DB02527 , would modulate basic fibroblast growth factor ( P09038 ) induction of MAPK activity ( P28482 ) and cell proliferation in human renal proximal tubular epithelial cells ( RPTEc ) and Madin-Darby canine kidney cells ( MDCK clone EI1 ) . DB01064 , but not P09038 , stimulated DB02527 production in RPTEc and MDCKEI1 cells . P09038 , isoproterenol , and 8-bromo- DB02527 alone increased P28482 activity in both cell types . However , isoproterenol and 8-bromo- DB02527 partially inhibited the P09038 induction of P28482 activity , but only isoproterenol inhibited the proliferation of both cell types . PD098059 ( 25 microM ) , an inhibitor of MAPK kinase ( Q02750 /2 ) , blocked the P09038 mitogenic effects , but did not affect the 8-bromo- DB02527 -induced mitogenic effects in MDCKEI1 cells . These findings suggest that activation of P28482 is required but not sufficient for mitogenesis in RTEc . We conclude that isoproterenol inhibits the growth-promoting effects of P09038 in RTEc via MEK-dependent and -independent pathways . DB00338 , a gastric proton pump inhibitor , inhibits melanogenesis by blocking Q04656 trafficking . DB00338 is a proton pump inhibitor used in the treatment of peptic ulcer disease and gastrosophageal reflux disease and acts by irreversibly blocking P20648 , a P-type H+/K+ ATPase in gastric parietal cells . We found that omeprazole and its closely related congeners inhibited melanogenesis at micromolar concentrations in B16 mouse melanoma cells , normal human epidermal melanocytes , and in a reconstructed human skin model . DB00338 topically applied to the skin of UV-irradiated human subjects significantly reduced pigment levels after 3 weeks compared with untreated controls . DB00338 had no significant inhibitory effect on the activities of purified human tyrosinase or on the mRNA levels of tyrosinase , dopachrome tautomerase , Pmel17 , or O75030 mRNA levels . Although melanocytes do not express P20648 , they do express Q04656 , a copper transporting P-type ATPase in the trans-Golgi network that is required for copper acquisition by tyrosinase . Q04656 relocalization from the trans-Golgi network to the plasma membrane in response to elevated copper concentrations in melanocytes was inhibited by omeprazole . DB00338 treatment increased the proportion of EndoH sensitive tyrosinase , indicating that tyrosinase maturation was impaired . In addition , omeprazole reduced tyrosinase protein abundance in the presence of cycloheximide , suggestive of increased degradation . Our findings are consistent with the hypothesis that omeprazole reduces melanogenesis by inhibiting Q04656 and by enhancing degradation of tyrosinase . Benzyl isothiocyanate ( BITC ) inhibits migration and invasion of human gastric cancer AGS cells via suppressing P29323 signal pathways . Metastasis suppressors and associated other regulators of cell motility play a critical initial role in tumor invasion and metastases . Benzyl isothiocyanate ( BITC ) is a hydrolysis compound of glucotropaeolin in dietary cruciferous vegetables . BITC has been found to exhibit prevention of cancers in laboratory animals and might also be chemoprotective in humans . Here , the purpose of this study was to investigate the effects of BITC on cell proliferation , migration , invasion and mitogen-activated protein kinase ( MAPK ) pathways of AGS human gastric cancer cells . Wound healing and Boyden chamber ( migration and invasion ) assays demonstrated that BITC exhibited an inhibitory effect on the abilities of migration and invasion in AGS cancer cells . BITC suppressed cell migration and invasion of AGS cells in a dose-dependent manner . Results from Western blotting indicated that BITC exerted an inhibitory effect on the P27361 /2 , Ras , P62993 , Rho A , P35228 , P35354 for causing the inhibitions of P08253 , -7 and -9 then followed by the inhibitions of invasion and migration of AGS cells in vitro . BITC also promoted O14733 , Q99759 , c-jun , P45983 /2 , P15692 , Sos1 , phosphoinositide 3-kinase ( PI3K ) , PKC , nuclear factor-kappaB ( NF-κB ) p65 in AGS cells . Results from real-time polymerized chain reaction ( PCR ) showed that BITC inhibited the gene expressions of P08253 ,-7 -9 , Q05397 , Q13464 and RhoA after BITC treatment for 24 and 48 hours in AGS cells . Taken together , the finding may provide new mechanisms and functions of BITC , which inhibit migration and invasion of human gastric cancer AGS cells . Chronically increased ciliary neurotrophic factor and fibroblast growth factor-2 expression after spinal contusion in rats . Demyelination and oligodendrocyte loss following spinal cord injury ( SCI ) are well documented . Recently , we showed oligodendrocyte progenitor cell ( OPC ) accumulation and robust oligodendrocyte genesis occurring along SCI lesion borders . We have since begun investigating potential mechanisms for this endogenous repair response . Here , we examined ciliary neurotrophic factor ( P26441 ) and fibroblast growth factor-2 ( P09038 ) expression , because both factors alter progenitor proliferation and differentiation and are increased in several CNS disorders . We hypothesized that P26441 and P09038 would increase after SCI , especially in regions of enhanced oligogenesis . First , P26441 protein was quantified using Western blots , which revealed that P26441 protein continually rose through 28 days post injury ( dpi ) . Next , by using immunohistochemistry , we examined the spatiotemporal expression of P26441 in cross-sections spanning the injury site . P26441 immunoreactivity was observed on astrocytes and oligodendrocytes in naïve and contused spinal cords . Significantly increased P26441 was detected in spared white and gray matter between 5 and 28 dpi compared with uninjured controls . By 28 dpi , P26441 expression was significantly higher along lesion borders compared with outlying spared tissue ; a similar distribution of phosphorylated P40763 , a transcription factor up-regulated by P26441 and to a lesser extent P09038 , was also detected . Because P26441 can potentiate P09038 expression , we examined the distribution of P09038 + cells . Significantly more P09038 + cells were noted along lesion borders at 7 and 28 dpi . Thus , both P26441 and P09038 are present in regions of elevated OPC proliferation and oligodendrocyte generation after SCI and therefore may play a role in injury-induced gliogenesis . Targeted deletion of P28482 in cardiomyocytes attenuates hypertrophic response but provokes pathological stress induced cardiac dysfunction . Mitogen-activated protein kinases ( MAPKs ) are involved in the regulation of cardiac hypertrophy and myocyte survival . Extracellular signal regulated protein kinase 1 and 2 ( P27361 /2 ) are key components in the MAPK signaling pathways . Dysfunction of P27361 /2 in congenital heart diseases ( Noonan syndrome and LEOPARD syndrome ) leads to cardiac hypertrophy . P28482 contributes 70 % of protein content to total P27361 /2 content in myocardium ; however , the specific role of P28482 in regulating cardiac hypertrophy is yet to be further defined . To investigate the specific role of P28482 played in the cardiomyocytes , we generated and examined mice with cardiomyocyte-specific deletion of the erk2 gene ( P28482 (cko) mice ) . Following short-term pathological hypertrophic stresses , the mutant mice showed attenuated hypertrophic remodeling characterized by a blunted increase in the cross-sectional area of individual myocytes , downregulation of hypertrophic foetal gene markers ( P01160 and DB04899 ) , and less interstitial fibrosis . However , increased cardiomyocyte apoptosis was observed . Upon prolonged stimulation , P28482 (cko) mice developed deterioration in cardiac function . However , absence of P28482 did not affect physiological hypertrophy induced by 4weeks of swimming exercise . These results revealed an essential role for P28482 in cardiomyocytes in the development of pathological hypertrophic remodeling and resistance to cell death . Flow cytometric analysis of mammalian glial cultures treated with methotrexate . DB00563 ( MTX ) is an antineoplastic drug that acts by competitive inhibition of the enzyme dihydrofolate reductase ( P00374 ) . MTX treatment of cultured cell lines leads to the emergence of resistant cell populations . Studies using stepwise selection procedures have demonstrated that MTX resistance conferred by overproduction of P00374 can be caused by P00374 gene amplification . We examined the effect of MTX on cells whose origin more closely approximates the in vivo condition by developing a culture system using dissociated brain tissue from 17-19 day old mouse embryos . At the first passage , cultures were divided into control and MTX groups . Cells were treated with the same or successively higher concentrations of MTX at each passage over a 3-4 month period . The first passage eliminated neurons and left a glial culture comprised of approximately 90 % astrocytes . We used the Fluorescence Activated Cell Sorter in conjunction with fluorescent dyes to measure P00374 content , DNA content , size , and viability of glial cells following MTX treatment . MTX-treated cells divided but grew more slowly and were larger than untreated cells . Stepwise selection in 30/60/90 nM or 60/120 nM MTX resulted in significant two- to threefold increases in fluorescence , and hence P00374 levels . Slot hybridizations assays demonstrated a threefold increase in P00374 gene copy number in the DNA from the 30/60/90 cultures . Thus , our findings were consistent with the results obtained from somatic cell lines , and lend support to the hypothesis that gene amplification may be a common mechanism for the acquisition of resistance in many types of cells . They also indicate that glial cells may be a specific target for cytotoxic effects of MTX on the central nervous system . Growth factors expression in patients with erosive esophagitis . Although the pathogenesis and treatment of erosive esophagitis ( EE ) is well recognized , little is known about the cellular and molecular mechanisms of mucosal healing in EE patients . In this pilot study , we enrolled typical EE patients to evaluate what kinds of growth factors and their receptors were activated in their injured esophageal mucosa . Forty endoscopically proved EE patients were consecutively enrolled . Messenger RNA expressions , which includes keratinocyte growth factor ( KGF ) and its receptor ( P21802 ) , epidermal growth factor ( P01133 ) and its receptor ( P00533 ) , hepatocyte growth factor ( P14210 ) and its receptor ( HGFR ) , basic fibroblast growth factor ( P09038 ) , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase ( P36551 ) -1 and P35354 , were measured using real-time polymerase chain reaction ( PCR ) . Data were compared between the injured EE mucosa and their normal esophageal mucosa above EE . The mRNA expressions of P14210 , HGFR , P01133 , P15692 , and P35354 , but not P00533 , KGF , P21802 , P09038 , and P23219 , were significantly increased in the injured mucosa of EE patients compared with those of normal mucosa ( P < 0.05 ) . The study found that P14210 , HGFR , P01133 , P15692 , and , P35354 are activated in the injured mucosa of EE patients ; their activation might be involved in mucosal repair and ulcer healing of EE . Phosphorylation of beta-arrestin2 regulates its function in internalization of beta(2)-adrenergic receptors . Beta-arrestins mediate agonist-dependent desensitization and internalization of G protein-coupled receptors . Previously , we have shown that phosphorylation of beta-arrestin1 by ERKs at DB00133 -412 regulates its association with clathrin and its function in promoting clathrin-mediated internalization of the receptor . In this paper we report that beta-arrestin2 is also phosphorylated , predominantly at residues DB00156 -383 and DB00133 -361 . DB01064 stimulation of the beta(2)-adrenergic receptor promotes dephosphorylation of beta-arrestin2 . Mutation of beta-arrestin2 phosphorylation sites to aspartic acid decreases the association of beta-arrestin2 with clathrin , thereby reducing its ability to promote internalization of the beta(2)-adrenergic receptor . Its ability to bind and desensitize the beta(2)-adrenergic receptor is , however , unaltered . These results suggest that , analogous to beta-arrestin1 , phosphorylation/dephosphorylation of beta-arrestin2 regulates clathrin-mediated internalization of the beta(2)-adrenergic receptor . In contrast to beta-arrestin1 , which is phosphorylated by P27361 and P28482 , phosphorylation of beta-arrestin2 at DB00156 -383 is shown to be mediated by casein kinase II . Recently , it has been reported that phosphorylation of visual arrestin at DB00133 -366 prevents its binding to clathrin . Thus it appears that the function of all arrestin family members in mediating internalization of G protein-coupled receptors is regulated by distinct phosphorylation/dephosphorylation mechanisms . Down-regulation of c-Cbl by morphine accounts for persistent P27361 /2 signaling in delta-opioid receptor-expressing HEK293 cells . Opioids display ligand-specific differences in the time course of P27361 /2 signaling . Whereas full agonists , like etorphine , induce only transient activation of P27361 /2 , the partial agonist morphine mediates persistent stimulation of mitogenic signaling . Here we report that in stably delta-opioid receptor ( Q8IXH6 ) -expressing HEK293 ( P29320 / Q8IXH6 ) cells , the transient nature of etorphine-induced P27361 /2 signaling is due to desensitization of epidermal growth factor ( P01133 ) receptor-mediated activation of the Ras/ P04049 / P27361 /2 cascade . Desensitization of P27361 /2 activity by etorphine is associated with down-regulation of P01133 receptors , an effect mediated by the ubiquitin ligase c-Cbl . In contrast , chronic morphine treatment failed to desensitize P01133 receptors , resulting in unimpeded P27361 /2 signaling . The failure of morphine to desensitize P27361 /2 signaling is mediated by persistent activation of c-Src , which induces degradation of c-Cbl . The role of c-Src in opioid-specific P27361 /2 signaling is further demonstrated by pretreatment of the cells with Q99463 and P12755 -I as well as overexpression of a dominant negative c-Src mutant ( c-Src(dn) ) or a c-Src-resistant c-Cbl mutant ( CblY3F ) , both of which facilitate desensitization of P27361 /2 signaling by morphine . Conversely , overexpression of c-Src as well as down-regulation of c-Cbl by small interfering RNA results in persistent etorphine-induced stimulation of P27361 /2 activity . Subcellular fractionation experiments finally attributed the ability of morphine to persistently activate c-Src to its redistribution from Triton X-100-insensitive membrane rafts to Q8IXH6 and P01133 receptor containing high density membrane compartments implicated in P27361 /2 signaling . These results demonstrate that agonist-specific differences in the temporal and spatial pattern of c-Src activation determine the kinetics of Q8IXH6 -mediated regulation of P27361 /2 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 . DB00563 and cytarabine inhibit progression of human lymphoma in NOD/SCID mice carrying a mutant dihydrofolate reductase and cytidine deaminase fusion gene . An SFG-based retroviral bicistronic vector containing a double-mutant dihydrofolate reductase-cytidine deaminase fusion cDNA ( F/S P00374 -CD ) with IRES-eGFP confers resistance to both methotrexate ( MTX ) and cytarabine ( ara-C ) . Two weeks after transplantation with marrow transduced with either a fusion or a control gene ( eGFP-IRES-NeoR ) , human lymphoma ( P12755 -DLCL-1 ) cells were injected sc into the flanks of nonobese diabetic/severe combined immune deficiency mice . In mock-transplanted mice , maximal tolerated dose ( MTD ) of posttransplant MTX/ara-C ( 15/10 mg/kg/day , x3 ) was unable to control tumor growth . Transfer of the fusion gene allowed doses of MTX/ara-C ( 25/15 mg/kg/day , x4 ) twofold higher than the MTD to be tolerated . The tumor burden defined the efficiency of posttransplant chemotherapy ; early treatment , 48 h after tumor inoculation , provided tumor-free survival , while starting treatment after having palpable tumor growth ( 7 days ) delayed tumor growth a median time of 28 days . In addition , the early treated group had higher gene expression in peripheral blood and marrow cells than the late treated group ( P < 0.05 ) , suggesting that early treatment allowed for enrichment of transduced marrow progenitors . These results encourage clinical studies using this retroviral fusion gene construct . Phosphorylation of the ARE-binding protein Q96EP5 by P28482 induces its dissociation from Q9NQZ3 . A protein in RAW 264.7 macrophages , which became phosphorylated in response to LPS ( lipopolysaccharide ) , was identified as the RNA-binding protein called Q96EP5 [ Q9NQZ3 ( deleted in azoospermia ) -associated protein 1 ] . The phosphorylation of this protein was prevented by specific inhibition of Q02750 [ MAPK ( mitogen-activated protein kinase ) kinase 1 ] , indicating that it was phosphorylated via the classical MAPK cascade . Further experiments showed that Q96EP5 was phosphorylated stoichiometrically in vitro by P28482 ( extracellular-signal-regulated protein kinase 2 ) at two DB00156 -Pro sequences ( Thr269 and Thr315 ) , and that both sites became phosphorylated in P29320 -293 ( human embryonic kidney 293 ) cells in response to PMA or P01133 ( epidermal growth factor ) , or RAW 264.7 macrophages in response to LPS . Phosphorylation induced by each stimulus was prevented by two structurally distinct inhibitors of Q02750 ( PD184352 and U0126 ) , demonstrating that Q96EP5 is a physiological substrate for P27361 / P28482 . The mutation of Thr269 and Thr315 to aspartate or the phosphorylation of these residues caused Q96EP5 to dissociate from its binding partner Q9NQZ3 . Q9NQZ3 interacts with PABP [ poly(A)-binding protein ] and thereby stimulates the translation of mRNAs containing short poly(A) tails [ Collier , Gorgoni , Loveridge , Cooke and Gray ( 2005 ) EMBO J. 24 , 2656-2666 ] . In the present study we have shown that Q9NQZ3 can not bind simultaneously to Q96EP5 and PABP , and suggest that the phosphorylation-induced dissociation of Q9NQZ3 and Q96EP5 may allow the former to stimulate translation by interacting with PABP . DB01095 enhances the inhibitory effects of a selective AT1 receptor blocker , valsartan , on atherosclerosis . We investigated the effects of a P04035 inhibitor ( statin ) on the inhibitory effects of an angiotensin II type-1 receptor ( AT1 ) blocker on atherosclerosis and explored cellular mechanisms . We gave apolipoprotein E null mice a high-cholesterol diet for 10 weeks and measured atherosclerotic plaque area and lipid deposition . Neither 1 mg/kg per day of valsartan nor 3 mg/kg per day of fluvastatin had any effect on blood pressure or cholesterol concentration ; however , both drugs decreased plaque area and lipid deposition after 10 weeks . We then reduced the doses of both drugs to 0.1 mg/kg per day and 1 mg/kg per day , respectively . At these doses , neither drug had an effect on atherosclerotic lesions . When both drugs were combined at these doses , a significant reduction in atherosclerotic lesions was observed . Similar inhibitory effects of valsartan or fluvastatin on the expressions of nicotinamide-adenine dinucleotide/nicotinamide-adenine dinucleotide phosphate oxidase subunits P13498 and p47phox , production of superoxide anion , the expression of monocyte chemoattractant protein-1 , and intercellular adhesion molecule-1 expression were observed . These results suggest that concomitant AT1 receptor and cholesterol biosynthesis blockade , particularly when given concomitantly , blunts oxidative stress and inflammation independent of blood pressure or cholesterol-related effects . 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 . Role of redox signaling in the autonomous proliferative response of endothelial cells to hypoxia . Endothelial cells exhibit an autonomous proliferative response to hypoxia , independent of paracrine effectors . In cultured endothelial cells of porcine aorta , we analyzed the signaling of this response , with a focus on the roles of redox signaling and the MEK/ P29323 pathway . Transient hypoxia ( 1 hour ) stimulated proliferation by 61+/-4 % ( n=16 ; P < 0.05 versus control ) , quantified after 24 hours normoxic postincubation . Hypoxia induced an activation of P28482 and of NAD(P)H oxidase and a burst of reactive oxygen species ( ROS ) , determined by DCF fluorescence . To inhibit the MEK/ P29323 pathway , we used PD 98059 ( PD , 20 micromol/L ) ; to downregulate NAD(P)H oxidase , we applied P13498 antisense oligonucleotides ; and to inhibit mitochondrial ROS generation , we used the ubiquinone derivate mitoQ ( MQ , 10 micromol/L ) . All three inhibitions suppressed the proliferative response : PD inhibited NAD(P)H oxidase activation ; P13498 antisense transfection did not inhibit P28482 activation , but suppressed ROS production ; and MQ inhibited P28482 activation and ROS production . The autonomous proliferative response depends on the MEK/ P29323 pathway and redox signaling steps upstream and downstream of P29323 . Located upstream is ROS generation by mitochondria , downstream is NAD(P)H oxidase . Interferon-gamma-induced dephosphorylation of P40763 and apoptosis are dependent on the P42345 pathway . Interferon-gamma ( P01579 ) exhibits diverse biological activities , including control of cell growth and tumor suppression . Here , we report that the treatment of M12 cells , a human metastatic prostate cancer cell line , with P01579 , resulted in marked inhibition of cell proliferation and induced apoptosis . These effects were not seen with either IFN-alpha or IFN-beta . M12 cells , like many other human cancer cells , contain constitutively activated signal transducer and activator of transcription 3 ( P40763 ) . The basal levels of both Akt and P27361 /2 phosphorylation are also markedly elevated in M12 cells . Strikingly , P01579 -induced apoptosis and growth inhibition of M12 cells were associated with persistent suppression of the constitutive tyrosine-phosphorylated P40763 ( pY- P40763 ) . The P01579 -induced dephosphorylation of pY- P40763 , however , was inhibited when the P42345 pathway was specifically blocked by rapamycin . Inhibition of PI-3K with low-dose LY294002 , or MAPK with PD98059 also suppressed the P42345 / P08133 S6k pathway , and correlated with the blockage of P01579 -induced dephosphorylation of pY- P40763 . Simultaneously , treatment with LY294002 , PD98059 , or rapamycin abolished P01579 -induced apoptosis in M12 cells . The inhibition of the P42345 pathway , however , did not affect P01579 -induced activation of P42224 pathway , and suppression of P42224 expression by siRNA had no effect on P01579 -induced dephosphorylation of pY- P40763 . Taken together , these results demonstrate that an intact P42345 pathway is critical for P01579 -induced suppression of pY- P40763 and apoptosis . Our study thus provides novel insights into the contributions of signaling pathways other than the classical JAK/ P42224 pathway in the anti-proliferative , proapoptotic actions of P01579 . AM2389 , a high-affinity , in vivo potent P21554 -receptor-selective cannabinergic ligand as evidenced by drug discrimination in rats and hypothermia testing in mice . RATIONALE : The endocannabinoid signaling system ( ECS ) has been targeted for developing novel therapeutics since ECS dysfunction has been implicated in various pathologies . Current focus is on chemical modifications of the hexahydrocannabinol ( HHC ) nabilone ( DB00486 (®) ) . OBJECTIVE : To characterize the novel , high-affinity cannabinoid receptor 1 ( CB(1)R ) HHC-ligand AM2389 [ 9β-hydroxy-3-(1-hexyl-cyclobut-1-yl)-hexahydrocannabinol in two rodent pre-clinical assays . MATERIALS AND METHODS : CB(1)R mediation of AM2389-induced hypothermia in mice was evaluated with AM251 , a CB(1)R-selective antagonist/inverse agonist . Additionally , two groups of rats discriminated the full cannabinergic aminoalkylindole AM5983 ( 0.18 and 0.56 mg/kg ) from vehicle 20 min post-injection in a two-choice operant conditioning task motivated by 0.1 % saccharin/water . Generalization/substitution tests were conducted with AM2389 , AM5983 , and Δ(9)-tetrahydrocannabinol ( Δ(9)-THC ) . RESULTS : Δ(9)-THC (30 mg/kg)-induced hypothermia exhibited a faster onset and shorter duration of action compared with AM2389 ( 0.1 and 0.3 mg/kg ) . AM251 ( 3 and 10 mg/kg ) attenuated/blocked hypothermia induced by 0.3 mg/kg AM2389 . In drug discrimination , the order of potency was AM2389 > AM5983 > Δ(9)-THC with ED(50) values of 0.0025 , 0.0571 , and 0.2635 mg/kg , respectively , in the low-dose condition . The corresponding ED(50) values in the high-dose condition were 0.0069 , 0.1246 , and 0.8438 mg/kg , respectively . Onset of the effects of AM2389 was slow with a protracted time-course ; the functional , perceptual in vivo half-life was approximately 17 h . CONCLUSIONS : This potent cannabinergic HHC exhibited a slow onset of action with a protracted time-course . The AM2389 chemotype appears well suited for further drug development , and AM2389 currently is used to probe behavioral consequences of sustained ECS activation . Definition of functional domains in P135gag-myb-ets and p48v-myb proteins required to maintain the response of neuroretina cells to basic fibroblast growth factor . The v-myb- and v-ets-containing E26 retrovirus induces the proliferation of chicken neuroretina ( P21554 ) cells in minimal medium . Proliferation of E26 P21554 cells is strongly stimulated by basic fibroblast growth factor ( P09038 ) . The v-myb-containing avian myeloblastosis virus also induces the proliferation of infected P21554 cells stimulated by P09038 . Both E26 P21554 and avian myeloblastosis virus P21554 cells are able to form colonies in soft agar in the presence of P09038 . This suggests that the v-myb product , a nuclear sequence-specific DNA-binding protein which activates gene expression in transient transfection assays , plays a role in the proliferative response of the infected P21554 cells . To determine the structure-function relationships of P135gag-myb-ets and p48v-myb , we have used deletion mutants expressed in retroviral vectors and have analyzed their effect on P21554 cell proliferation as well as their effect on the P21554 cell response to P09038 . We show that v-ets is not required for P09038 stimulation but increases the proliferation of P21554 cells in minimal medium . In the v-myb mutants , the gag sequences derived from the helper virus increase the potency of the myb gene . The carboxyl-terminal domain required for the growth and transformation of myeloid cells and needed for maximal trans-activation in transient DNA transfection assays in fibroblasts was not required for the growth and P09038 response of P21554 cells . In contrast , the domain encompassing amino acids 240 to 301 ( containing part of the transcriptional activation domain of v-myb ) was absolutely required for the response of P21554 cells to P09038 and could be functionally replaced by the carboxyl-terminal transcriptional activation domain of the VP16 protein of herpes simplex virus . Angiotensin II and basic fibroblast growth factor mitogenic pathways in human fetal mesangial cells . Angiotensin II ( Ang II ) and basic fibroblast growth factor ( P09038 / P09038 ) play relevant roles in renal development . Since the signaling pathways modulating the mitogenic effects of Ang II and P09038 in human fetal mesangial cells ( HFMc ) are not clearly defined , we carried out experiments to determine whether they would exert their mitogenic effects by modulating the activity of the mitogen-activated protein kinases ( MAPK ) [ extracellular signal-regulated kinase-2 ( P28482 ) ] and DB02527 signaling pathways . In confluent HFMc , P09038 ( 20 ng/mL ) induced a significant 4-fold increase in P28482 activity and [ 3H ] -thymidine incorporation ( 6-fold ) . In contrast , under similar tissue culture conditions , Ang II ( 10(-6) M ) induced a more modest increase in P28482 activity ( 2-fold ) and [ 3H ] -thymidine incorporation ( 35 +/- 4 % ) . The mitogen-activated protein kinase kinase-1 ( MEK-1 ) inhibitor PD098059 ( 25 microM ) almost completely abolished the P09038 -induced proliferation in HFMc but did not significantly affect Ang II proliferative effects . In the presence of the DB02527 elevating agent isoproterenol , Ang II and P09038 induced opposite changes in DB02527 accumulation and cell growth . DB01064 inhibited the basal and P09038 -induced proliferation of HFMc through a MEK-1/2-independent pathway that included the accumulation of DB02527 . In contrast , isoproterenol increased Ang II mitogenic effects in correlation with a reduction in DB02527 accumulation . We conclude that Ang II and P09038 modulate the proliferation of HFMc through the stimulation of different MEK-1/2-dependent and independent signaling pathways . Activation of MEK-1/2 is required but not sufficient for mitogenesis in HFMc . The accumulation of DB02527 in HFMc counteracts the mitogenic effects of P09038 by a MEK-1/2-independent pathway . High-level synthesis of recombinant murine endostatin in Chinese hamster ovary cells . Endostatin , a carboxy-terminal fragment of collagen XVIII , has been shown to act as an anti-angiogenic agent that specifically inhibits proliferation of endothelial cells and growth of various primary tumors . Here , we describe the expression by Chinese hamster ovary ( CHO ) cells of murine endostatin and of a tagged-fusion protein , (his)6-met-endostatin . A dicistronic mRNA expression vector was utilized in which endostatin cDNA was inserted upstream of the amplifiable marker gene , dihydrofolate reductase ( P00374 ) . After transfection of the expression vectors , stepwise increments in methotrexate levels in the culture medium were applied , promoting gene amplification and increasing expression levels of the proteins of interest . The expression level of secreted native endostatin was about 78 microg/mL while the one for secreted (his)6-met-endostatin was about 114 microg/mL , for the best expressing clones . Characterization of physico-chemical and immunological activities of the proteins was performed using SDS-PAGE and Western blotting . The biological activities of recombinant endostatins were tested with a cow pulmonary artery endothelial ( C-PAE ) cell proliferation assay . Both recombinant endostatin and (his)6-met-endostatin inhibited , in a dose-dependent fashion , growth of C-PAE cells stimulated by basic fibroblast growth factor ( P09038 ) . Atrial natriuretic peptide : a possible mediator involved in dexamethasone 's inhibition of cell proliferation in multiple myeloma . Atrial natriuretic peptide ( P01160 ) has been recognized for several decades for its role of regulating blood pressure . Recently , cumulating evidences show that P01160 plays an anticancer role in various solid tumors via blocking the kinase cascade of Ras- Q02750 /2- P27361 /2 with the result of inhibition of DNA synthesis . P01160 , as well as its receptors ( P16066 and P17342 ) has been identified present in the embryonic stem cell and a wide range of cancer cells . Various lymphoid organs , such as lymph nodes , have been detected the presence of P01160 . Multiple myeloma ( MM ) , though the therapies have evolved significantly , is still an incurable disease as B lymphocyte cell neoplasm . Dexamethasone is the cornerstone in treatment of MM via inactivation of Ras- Q02750 /2- P27361 /2 cascade reaction . Coincidently , dexamethasone can increase the expression of P01160 markedly . Nevertheless , the role of P01160 in MM is unclear . Based on these results above , we raise the hypothesis that P01160 is involved in mediating dexamethasone 's inhibition of proliferation in MM cells , which suggests that P01160 may be a potential agent to treat MM . DB00104 prevents growth factor-induced proliferation of bovine retinal endothelial cells under hypoxia . Ocular diseases such as proliferative diabetic retinopathy are the major cause of blindness in industrialized countries . The main pathologic features of these diseases are hypoxia and overproduction of growth factors resulting in pathologic proliferation of endothelial cells and new vessel formation . Particularly , hypoxia and growth factors , such as P15692 , DB01277 , P09038 and TGF beta(2) , show a complex interaction in the onset and progression of the diseases . Therefore , to date , most therapeutic strategies for proliferative retinopathies have targeted proliferation of endothelial cells evoked by growth factors . Recently , a synthetic analog of somatostatin , octreotide , has been shown to inhibit the proliferation of various cells in vitro , including endothelial cells . In this study , we have investigated the proliferative response of bovine retinal endothelial cells ( BREC ) to growth factors under hypoxic conditions and the modulation by octreotide . We found a dose-dependent increase of cell proliferation with P15692 , DB01277 and P09038 , and inhibition of hypoxia-induced cell proliferation with TGF beta(2) . Moreover , growth factor-induced , but not hypoxia-induced , cell proliferation was attenuated in the presence of octreotide . In contrast , TGF beta(2) abolished hypoxia-induced BREC proliferation . Similar to octreotide BIM23027 , a somatastatin receptor subtype 2 ( P30874 ) receptor agonist was able to attenuate the growth factor-induced proliferation of BREC expressing mRNA and protein for P30874 . Therefore , we postulate that octreotide exerts its effects mainly through binding to the P30874 . Taken together , our findings point to octreotide as a promising candidate for the treatment of eye disorders involving growth factor-dependent proliferation of endothelial cells .