Renal disease is a common complication of diabetes. The initiating events in diabetic nephropathy are triggered by hyperglycemia and, possibly, advanced glycation end products. Subsequently, excess levels of vasoactive peptides (especially endothelin-1 (ET-1)) accumulate in the diabetic kidney, and there is evidence that these peptides mediate many of the pathophysiological changes associated with diabetic renal disease. These changes include an excess deposition of extracellular matrix proteins into the glomerular basement membrane and renal mesangial cell hypertrophy. Our transcriptional profiling studies have revealed that the p8 gene, which encodes a putative basic helix-loop-helix protein, is strongly induced in ET-1-treated renal mesangial cells and in an animal model of diabetic nephropathy. RNA interference experiments indicated that the p8 gene is required for ET-1-induced mesangial cell hypertrophy. Here, we show that the p8 polypeptide is a phosphoprotein subject to constitutive degradation by the ubiquitin/proteasome system. This degradation is mediated by phosphatidylinositol 3-kinase and protein kinase B/Akt. By contrast, stabilization of the p8 protein requires glycogen synthase kinase-3. Finally, short interfering RNA-mediated RNA interference experiments indicated that ET-1-stimulated mesangial cell hypertrophy and p8 mRNA induction require the NFAT4 transcription factor. Thus, p8 levels in the cell are likely maintained by a balance between signal-dependent transcriptional induction and proteolysis. Renal disease is a common complication of diabetes. The initiating events in diabetic nephropathy are triggered by hyperglycemia and, possibly, advanced glycation end products. Subsequently, excess levels of vasoactive peptides (especially endothelin-1 (ET-1)) accumulate in the diabetic kidney, and there is evidence that these peptides mediate many of the pathophysiological changes associated with diabetic renal disease. These changes include an excess deposition of extracellular matrix proteins into the glomerular basement membrane and renal mesangial cell hypertrophy. Our transcriptional profiling studies have revealed that the p8 gene, which encodes a putative basic helix-loop-helix protein, is strongly induced in ET-1-treated renal mesangial cells and in an animal model of diabetic nephropathy. RNA interference experiments indicated that the p8 gene is required for ET-1-induced mesangial cell hypertrophy. Here, we show that the p8 polypeptide is a phosphoprotein subject to constitutive degradation by the ubiquitin/proteasome system. This degradation is mediated by phosphatidylinositol 3-kinase and protein kinase B/Akt. By contrast, stabilization of the p8 protein requires glycogen synthase kinase-3. Finally, short interfering RNA-mediated RNA interference experiments indicated that ET-1-stimulated mesangial cell hypertrophy and p8 mRNA induction require the NFAT4 transcription factor. Thus, p8 levels in the cell are likely maintained by a balance between signal-dependent transcriptional induction and proteolysis. Diabetic nephropathy is a common complication of both type I and II diabetes and represents the major cause of end stage renal failure in the Western World (1Fine L.G. Norman J.T. Kujubu D.A. Knecht A. Seldin D.W. Geibisch G. The Kidney, Physiology and Pathophysiology. Raven Press, Ltd., New York1992: 3113-3134Google Scholar). The renal disease characteristic of diabetes mellitus arises relatively quickly with the onset of frank hyperglycemia and is marked by elevations in circulating vasoactive peptides, glomerular mesangial cell hypertrophy, and proliferation as well as the excess deposition of extracellular matrix proteins into the glomerular basement membrane (2Bonventre J.V. Force T. Curr. Opin. Nephrol. Hypertens. 1998; 7: 425-433Crossref PubMed Scopus (27) Google Scholar, 3Wolf G. J. Am. Soc. Nephrol. 2002; 13: 2611-2613PubMed Google Scholar). Mesangial cell hypertrophy is characterized at the cellular level as an increase in overall protein synthesis in the absence of a concomitant increase in overall DNA synthesis. Multiple extracellular stimuli are thought to be involved in the pathophysiology of diabetic mesangial cell hypertrophy. Prominent among these are vasoactive peptides such as endothelin-1 (ET-1), 1The abbreviations used are: ET-1, endothelin-1; MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositol 3-kinase; Ub, ubiquitin; ERK, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase; NFAT, nuclear factor of activated T cells; RNAi, RNA interference; GSK3, glycogen synthase kinase-3; FBS, fetal bovine serum; EGFP, enhanced green fluorescent protein; GFP, green fluorescent protein; Mops, 4-morpholinepropanesulfonic acid; siRNA, small interfering RNA. vasopressin, angiotensin II, and transforming growth factor-β (2Bonventre J.V. Force T. Curr. Opin. Nephrol. Hypertens. 1998; 7: 425-433Crossref PubMed Scopus (27) Google Scholar, 4Sorokin A. Kohan D.E. Am. J. Physiol. 2003; 285: F579-F589Crossref PubMed Scopus (113) Google Scholar, 5Wang Y. Su B. Sah V.P. Brown J.H. Han J. Chien K.R. J. Biol. Chem. 1998; 273: 5423-5426Abstract Full Text Full Text PDF PubMed Scopus (297) Google Scholar, 6Wang Y. Huang S. Sah V.P. Ross Jr., J. Brown J.H. Han J. Chien K.R. J. Biol. Chem. 1998; 273: 2161-2168Abstract Full Text Full Text PDF PubMed Scopus (748) Google Scholar). Our recent findings indicate that renal mesangial cell hypertrophy is controlled by mechanisms similar to those governing cardiomyocyte hypertrophy (9Goruppi S. Bonventre J.V. Kyriakis J.M. EMBO J. 2002; 21: 5427-5436Crossref PubMed Scopus (67) Google Scholar). In particular, in addition to the recruitment of MAPKs, mesangial cell hypertrophy requires activation of the phosphatidylinositol 3-kinase (PI3K) pathway (9Goruppi S. Bonventre J.V. Kyriakis J.M. EMBO J. 2002; 21: 5427-5436Crossref PubMed Scopus (67) Google Scholar). Our studies have been aimed at the identification of mechanisms coupling signaling pathways with more distal elements that trigger renal mesangial cell hypertrophy. Using a combined pharmacological and transcriptional profiling approach, we have identified genes induced by ET-1 after the period of treatment needed to trigger hypertrophy. Seven genes were identified; of these, one transcript, encoding the small basic helix-loop-helix protein p8, was strikingly and stably induced by ET-1 (9Goruppi S. Bonventre J.V. Kyriakis J.M. EMBO J. 2002; 21: 5427-5436Crossref PubMed Scopus (67) Google Scholar). The p8 gene has been conserved evolutionarily, with homologs found in man, rat, mouse, and Xenopus. p8 was initially isolated as a gene strongly induced during acute pancreatitis (10Mallo G.V. Fiedler F. Calvo E.L. Ortiz E.M. Vasseur S. Keim V. Morisset J. Iovanna J.L. J. Biol. Chem. 1997; 272: 32360-32369Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar, 11Vasseur S. Mallo G.V. Fiedler F. Bodeker H. Canepa E. Moreno S. Iovanna J.L. Eur. J. Biochem. 1999; 259: 670-675Crossref PubMed Scopus (97) Google Scholar, 12Igarashi T. Kuroda H. Takahashi S. Asashima M. Dev. Growth Differ. 2001; 43: 693-698Crossref PubMed Scopus (25) Google Scholar). In several cell lines, the p8 gene is transiently induced in response to stress and thus may be part of a general defense mechanism protecting against cellular injury (10Mallo G.V. Fiedler F. Calvo E.L. Ortiz E.M. Vasseur S. Keim V. Morisset J. Iovanna J.L. J. Biol. Chem. 1997; 272: 32360-32369Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar, 11Vasseur S. Mallo G.V. Fiedler F. Bodeker H. Canepa E. Moreno S. Iovanna J.L. Eur. J. Biochem. 1999; 259: 670-675Crossref PubMed Scopus (97) Google Scholar). Consistent with this, targeted disruption of the murine p8 gene, although not lethal, does result in higher mortality in the lipopolysaccharide injection model of sepsis (13Vasseur S. Hoffmeister A. Garcia-Montero A. Barthet M. Saint-Michel L. Berthezene P. Fiedler F. Closa D. Dagorn J.C. Iovanna J.L. BMC Gastroenterol. 2003; http://www.biomedcentral.com/1471-230X/3/25PubMed Google Scholar). Other studies have implicated p8 gene expression with metastatic potential (14Ree A.H. Tvermyr M. Engebraaten O. Rooman M. Rosok O. Hovig E. Meza-Zepeda L.A. Bruland O.S. Fodstad O. Cancer Res. 1999; 59: 4675-4680PubMed Google Scholar), and the p8 gene may also be involved in the control of cell proliferation, although the precise function of p8 in cell proliferation is unclear. Thus, disruption of the p8 gene suppresses transformation associated with ectopic expression of ras and adenoviral E1A, blunting the growth of these transformed cells in soft agar and preventing the formation of tumors in mice injected with ras/E1A-transformed p8–/– cells (15Vasseur S. Hoffmeister A. Garcia S. Bagnis C. Dagorn J.C. Iovanna J.L. EMBO Rep. 2002; 3: 165-170Crossref PubMed Scopus (69) Google Scholar). By contrast, p8–/– cells proliferate more rapidly in culture and are resistant to chemical stress-induced apoptosis (16Vasseur S. Hoffmeister A. Garcia-Montero A. Mallo G.V. Fieil R. Kühbander S. Dagorn J.C. Iovanna J.L. Oncogene. 2002; 21: 1685-1694Crossref PubMed Scopus (81) Google Scholar). The product of the human p8 gene is an 82-amino acid protein with no significant homology to any other known eukaryotic protein. Analysis of the primary structure of p8 revealed a canonical bipartite nuclear localization signal and a potential DNA interaction motif (see Fig. 1A) (13Vasseur S. Hoffmeister A. Garcia-Montero A. Barthet M. Saint-Michel L. Berthezene P. Fiedler F. Closa D. Dagorn J.C. Iovanna J.L. BMC Gastroenterol. 2003; http://www.biomedcentral.com/1471-230X/3/25PubMed Google Scholar). Accordingly, p8 has been to in to an interaction enhanced in by of the protein with protein kinase Mallo G.V. C. L. J.M. M. Canepa E. Moreno S. J.L. Iovanna J.L. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). Consistent with the that p8 is by of the acid of p8 is of Mallo G.V. C. L. J.M. M. Canepa E. Moreno S. J.L. Iovanna J.L. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). In the p8 protein an N-terminal of p8 levels by the (see Fig. 1A) M. Biochem. 21: Full Text PDF PubMed Scopus Google Scholar). have the renal mesangial cell signaling events activated by ET-1 that are required for hypertrophy and found that hypertrophy requires activation of the and as well as proteins (9Goruppi S. Bonventre J.V. Kyriakis J.M. EMBO J. 2002; 21: 5427-5436Crossref PubMed Scopus (67) Google Scholar). ET-1 induction of the p8 gene requires activation of these signaling The p8 gene is also strongly induced in the of diabetic with RNA interference to mesangial cell p8 mRNA identified the p8 gene as a in the ET-1-stimulated transcriptional that mesangial cell hypertrophy (9Goruppi S. Bonventre J.V. Kyriakis J.M. EMBO J. 2002; 21: 5427-5436Crossref PubMed Scopus (67) Google Scholar). there is a of the of p8 gene expression and of the putative of the p8 gene is known the of the p8 polypeptide of the p8 protein levels in the In studies of the mesangial cell p8 we were to that p8 was cells were with of the system. these we a ET-1-stimulated increase in the p8 protein; the of increase was the to and we were to not p8 protein as with p8 is by extracellular signaling Here, we show that the p8 protein is in found that the of p8 polypeptide levels to the of p8 p8 is a nuclear protein that is a and degradation is by the Accordingly, p8 requires in GSK3, the of which is by also p8 in of a the addition of a the p8 protein and that of p8 is mediated by the The enhanced the levels of and a p8 by a that be with Finally, experiments indicated that ET-1-induced mesangial cell hypertrophy and p8 mRNA induction require a transcription factor that is by and activated by renal mesangial cells were isolated as (9Goruppi S. Bonventre J.V. Kyriakis J.M. EMBO J. 2002; 21: 5427-5436Crossref PubMed Scopus (67) Google Scholar). Mesangial cells were in and fetal bovine cells were in and ET-1, and were was studies of and cells were as S. E. B. C. Biol. 1997; PubMed Scopus Google Scholar). DNA and was by by the of the human p8 and a short for by a The was into the was by human p8 at the of the enhanced green fluorescent protein encoding and have been M. Dev. 1998; PubMed Scopus Google Scholar). and were and Western cells were at were as by the were used after and were to the to the In cells were in of of protein were was with against NFAT4 were with the enhanced system. Mesangial cells at were for in and and for with ET-1 in the absence of were in and of proteins were to and with p8, the membrane was the treatment of the p8 protein with cells were with as the cells were in of and The p8 protein was for at of The were with with and and with The p8 protein was into was The were at for with in the absence of which is required for were with The were to and with In experiments of p8 was with and the cellular as The were and the kinase cells were with encoding The cells were with and in of and of protein were with of for at with of protein The were with and with kinase and and for at with of p8 protein, and of were by the addition of by and to In with and cells as were for in of were with and as in of and of were with of for at with of protein and the were by and to Mesangial cells were for in a with ET-1, and for with with and were in of and with of as was as J. T. Scholar). RNA RNA the were The for p8 has been (9Goruppi S. Bonventre J.V. Kyriakis J.M. EMBO J. 2002; 21: 5427-5436Crossref PubMed Scopus (67) Google Scholar). and of the were to the for were as by J. A. T. 2001; PubMed Scopus Google Scholar). were into mesangial cells at of and of an with the siRNA, mesangial cells were for in and Analysis of ET-1-induced mesangial cell hypertrophy has been (9Goruppi S. Bonventre J.V. Kyriakis J.M. EMBO J. 2002; 21: 5427-5436Crossref PubMed Scopus (67) Google Scholar). of p8 by the have that p8 mRNA expression is rapidly induced by ET-1 during the onset of mesangial cell hypertrophy (9Goruppi S. Bonventre J.V. Kyriakis J.M. EMBO J. 2002; 21: 5427-5436Crossref PubMed Scopus (67) Google Scholar). is induction is in in the in levels of p8 protein. we were to p8 protein in of mesangial cells by after treatment with ET-1 were to mesangial cell p8 after of cells that been with In p8 was with and not with ET-1 treatment for which is to p8 mRNA (see Fig. (9Goruppi S. Bonventre J.V. Kyriakis J.M. EMBO J. 2002; 21: 5427-5436Crossref PubMed Scopus (67) Google Scholar), not trigger in the p8 polypeptide Thus, ET-1 a increase in p8 mRNA to trigger a concomitant increase in the p8 protein and and the in the p8 protein, we p8 be of the primary of p8 indicated the of a are in many that are subject to degradation by the M. Biochem. 21: Full Text PDF PubMed Scopus Google Scholar). Thus, we the p8 protein levels of the G. S. PubMed Scopus Google Scholar). of mesangial cells with of p8 by these we a increase in the p8 protein treatment with ET-1 that increase was of cells and is unclear. is Fig. that p8 was by the system. p8 in cells in a similar Thus, Fig. that p8 was in not in after ectopic p8 protein levels The addition of to the culture a significant of the p8 polypeptide of p8 levels by the system. is to proteins a between a in the polypeptide for proteins for and a in the protein. found that p8 was in in cells p8 in cells p8 and Fig. which p8 protein that p8 at By contrast, at an increase in of the of the Thus, to be not is to the overall expression of p8 to the that p8 is to be these strongly indicate that p8 is by the system. p8 a of the primary structure of p8 revealed a canonical bipartite nuclear localization signal and a potential DNA interaction motif 1A) (13Vasseur S. Hoffmeister A. Garcia-Montero A. Barthet M. Saint-Michel L. Berthezene P. Fiedler F. Closa D. Dagorn J.C. Iovanna J.L. BMC Gastroenterol. 2003; http://www.biomedcentral.com/1471-230X/3/25PubMed Google Scholar). thus the protein localization by in cell N-terminal the p8 protein, resistant to as a with GFP, p8 was in the nuclear of both and cells in absence of The control protein was the cell This cellular localization was not by of the cells with growth factor after stress with not these thus strongly that p8 in the nuclear p8 a of by is a protein with a of that are potential for protein Consistent with this, p8 has been to be an in for protein kinase and Mallo G.V. C. L. J.M. M. Canepa E. Moreno S. J.L. Iovanna J.L. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). thus p8 is in the of p8, we to p8 in were with and with p8 was with the and p8 proteins were and p8 at an of more the acid was to of the protein, we the protein in with was cells and with in the absence of a for P. Biochem. J. T. PubMed Scopus Google Scholar). the the were with and the were by In the of enhanced the of p8 be that the p8 polypeptide more that the of p8 be to p8 is at levels in and after ectopic is to the p8 protein in the absence of of the are in a by extracellular signaling pathways M. Y. PubMed Scopus Google Scholar). Accordingly, we to the signaling pathways known to p8 mRNA levels also the of the p8 protein in Thus, cells were with and for with a of protein and S. A. S. V. E. Biochem. J. 1999; PubMed Scopus Google Scholar). rapidly p8 to a at which the protein was This was with that of a the degradation of p8 has been to be a in for protein kinase and in is (15Vasseur S. Hoffmeister A. Garcia S. Bagnis C. Dagorn J.C. Iovanna J.L. EMBO Rep. 2002; 3: 165-170Crossref PubMed Scopus (69) Google Scholar, S. Hoffmeister A. Garcia-Montero A. Mallo G.V. Fieil R. Kühbander S. Dagorn J.C. Iovanna J.L. Oncogene. 2002; 21: 1685-1694Crossref PubMed Scopus (81) Google Scholar, Mallo G.V. C. L. J.M. M. 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PubMed Scopus Google Scholar), an of an signaling pathway of cell were by Western Consistent with the that recruitment of p8, signaling with p8 be a Fig. that not was to the p8 protein. strongly that recruitment of of to of the p8 protein. ET-1 of p8 and Renal Mesangial NFAT4 cardiomyocyte hypertrophy a and mechanism T. R. F. A. G. 1999; 7: Google Scholar, Res. PubMed Scopus Google Scholar, B. J. J. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, Res. PubMed Scopus Google Scholar). is that ET-1 recruitment of and J. J.M. S. A. 2002; PubMed Scopus Google Scholar, P. M. A. PubMed Scopus Google Scholar). This of NFAT4 J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, A. C. 1997; PubMed Scopus Google Scholar). ET-1 also in the protein the of NFAT4 to the genes for hypertrophy J. J.M. S. A. 2002; PubMed Scopus Google Scholar, B. J. J. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, A. C. 1997; PubMed Scopus Google Scholar, S. G. H. T. A. A. J. R. A. Force T. J. Biol. PubMed Scopus Google Scholar). have that a protein is to ET-1-induced mesangial cell hypertrophy as well as induction of the p8 gene (9Goruppi S. Bonventre J.V. Kyriakis J.M. EMBO J. 2002; 21: 5427-5436Crossref PubMed Scopus (67) Google Scholar). have also that p8 gene induction is required for mesangial cell hypertrophy (9Goruppi S. Bonventre J.V. Kyriakis J.M. EMBO J. 2002; 21: 5427-5436Crossref PubMed Scopus (67) Google Scholar). These findings to NFAT4 is required for mesangial cell hypertrophy. cell mediated by to NFAT4 p8 were into mesangial NFAT4 expression was by Western of NFAT4 into mesangial cells NFAT4 protein levels RNA to a used as a control was NFAT4 levels Fig. that of NFAT4 ET-1-induced renal mesangial hypertrophy. to the human p8 gene, which no renal mesangial cell p8 mRNA not to ET-1-stimulated renal mesangial cell hypertrophy p8 as a gene induced in mesangial cells by ET-1 and required for ET-1-stimulated hypertrophy (9Goruppi S. Bonventre J.V. Kyriakis J.M. EMBO J. 2002; 21: 5427-5436Crossref PubMed Scopus (67) Google Scholar), we to p8 gene induction requires treatment of renal mesangial cells with for the p8 gene both and ET-1-induced p8 gene expression of NFAT4 also ET-1 induction of the p8 gene The in Fig. and strongly indicate that NFAT4 is required for both ET-1-induced mesangial cell hypertrophy and p8 gene with that the p8 gene is required for ET-1-stimulated mesangial cell hypertrophy (9Goruppi S. Bonventre J.V. Kyriakis J.M. EMBO J. 2002; 21: 5427-5436Crossref PubMed Scopus (67) Google Scholar), these findings are with the that mesangial cell hypertrophy requires in part induction of p8 Our an found that p8 mRNA is rapidly and stably induced by ET-1 and that p8 is required for ET-1-stimulated renal mesangial cell hypertrophy (9Goruppi S. Bonventre J.V. Kyriakis J.M. EMBO J. 2002; 21: 5427-5436Crossref PubMed Scopus (67) Google Scholar). Our findings and indicate that induction of p8 mRNA and mesangial cell hypertrophy require recruitment of the pathway and the other studies of the p8 protein indicate that is in subject to degradation by the we found that p8 protein is in mesangial cells is not of the cells with we also that the of GSK3, the degradation of Thus, we found that the of the p8 protein, likely to of that The and of in to p8 Thus, although p8 is required for ET-1-stimulated hypertrophy, the common signaling pathways p8 gene transcription and p8 protein function at with ET-1 both a increase in p8 mRNA and a and degradation of the p8 protein The of is that p8 protein levels during ET-1 these is to that level of p8 protein part of the mechanism by which ET-1 mesangial cell hypertrophy does ET-1 trigger both degradation of renal mesangial cell p8 protein and of p8 is that p8 degradation is part of a general stress response the is to in response to and the p8 protein is to of The induction of p8 mRNA be to p8 protein levels during the degradation of p8 and induction be of mesangial cell p8 mRNA is of ET-1 By contrast, activation of protein kinase and of of p8 is more (9Goruppi S. Bonventre J.V. Kyriakis J.M. EMBO J. 2002; 21: 5427-5436Crossref PubMed Scopus (67) Google Scholar). of the p8 protein be required for the more acute of ET-1, of p8, to ET-1-stimulated induction of p8 function in the more of ET-1 such as hypertrophy. as ET-1 activation of NFAT4 to be required for p8 mRNA induction we not that p8 polypeptide degradation as a trigger for induction of p8 is likely that these pathways of for the of NFAT4 to the p8 both the and human p8 a of the we not a similar is conserved in Thus, although NFAT4 is for ET-1-stimulated mesangial cell hypertrophy, is NFAT4 the p8 p8 mRNA induction p8 is a putative basic helix-loop-helix protein, the function of which p8 mRNA is induced during acute pancreatitis (10Mallo G.V. Fiedler F. Calvo E.L. Ortiz E.M. Vasseur S. Keim V. Morisset J. Iovanna J.L. J. Biol. Chem. 1997; 272: 32360-32369Abstract Full Text Full Text PDF PubMed Scopus (202) Google and is in (14Ree A.H. Tvermyr M. Engebraaten O. Rooman M. Rosok O. Hovig E. Meza-Zepeda L.A. Bruland O.S. Fodstad O. Cancer Res. 1999; 59: 4675-4680PubMed Google Scholar). These findings have a for p8 in stress and Consistent with a function in proliferation, disruption of the murine p8 gene suppresses the as soft agar formation and of of transforming ras and adenoviral (15Vasseur S. Hoffmeister A. Garcia S. Bagnis C. Dagorn J.C. Iovanna J.L. EMBO Rep. 2002; 3: 165-170Crossref PubMed Scopus (69) Google Scholar). By contrast, p8–/– proliferate more quickly in culture cells (15Vasseur S. Hoffmeister A. Garcia S. Bagnis C. Dagorn J.C. Iovanna J.L. EMBO Rep. 2002; 3: 165-170Crossref PubMed Scopus (69) Google Scholar, S. Hoffmeister A. Garcia-Montero A. Mallo G.V. Fieil R. Kühbander S. Dagorn J.C. Iovanna J.L. Oncogene. 2002; 21: 1685-1694Crossref PubMed Scopus (81) Google Scholar). is that p8 is for p8 is a nuclear protein, and there is evidence that p8 in transcriptional Thus, that p8 to a polypeptide in and the transcription factor A. A. Vasseur S. Mallo G.V. H. B. Dagorn J.C. Moreno S. Iovanna J.L. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). and gene experiments that p8 of is required during for of the renal of hypertrophy is the of genes B. J. J. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, Res. PubMed Scopus Google Scholar, 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). be to p8 function in mesangial cell hypertrophy. The cellular events that in hypertrophy likely require and changes in gene expression to stimuli B. J. J. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, Res. PubMed Scopus Google Scholar). p8 is the that we have found to be stably induced during the of diabetic nephropathy (9Goruppi S. Bonventre J.V. Kyriakis J.M. EMBO J. 2002; 21: 5427-5436Crossref PubMed Scopus (67) Google Scholar). The other is gene which encodes a protein implicated in the recruitment of the pathway and in the of and growth factor activation of A. D.A. A. Force T. Bonventre J.V. Kyriakis J.M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus (113) Google Scholar). These that gene to cell proliferation and to the cell to to stress J.M. J. Physiol. 2001; PubMed Scopus Google Scholar). ET-1 of mesangial protein to cell proliferation (9Goruppi S. Bonventre J.V. Kyriakis J.M. EMBO J. 2002; 21: 5427-5436Crossref PubMed Scopus (67) Google Scholar). Our and that p8 is required for the enhanced protein synthesis characteristic of hypertrophy.
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