Key points are not available for this paper at this time.
The hepatic stellate cell (HSC) is the predominant cell type responsible for excess collagen deposition during liver fibrosis. Both transforming growth factor-β (TGF-β), the most potent fibrogenic cytokine for HSCs, which classically activates Smad signaling, and p38 MAPK signaling have been shown to influence collagen gene expression; however, the relative contribution and mechanisms that these two signaling pathways have in regulating collagen gene expression have not been investigated. The aim of this study was to investigate the relative roles and mechanisms of both Smad and p38 MAPK signaling in α1(I) collagen gene expression in HSCs. Inhibiting either p38 MAPK or Smad signaling reduced α1(I) collagen mRNA expression in untreated or TGF-β-treated HSCs, and when both signaling pathways were simultaneously inhibited, α1(I) collagen gene expression was essentially blocked. Both signaling pathways were found to independently and additively increase α1(I) collagen gene expression by transcriptional mechanisms. TGF-β treatment increased α1(I) collagen mRNA half-life, mediated by increased stability of α1(I) collagen mRNA through p38 MAPK signaling but not through Smad signaling. In conclusion, both p38 MAPK and Smad signaling independently and additively regulate α1(I) collagen gene expression by transcriptional activation, whereas p38 MAPK and not Smad signaling increased α1(I) collagen mRNA stability. The hepatic stellate cell (HSC) is the predominant cell type responsible for excess collagen deposition during liver fibrosis. Both transforming growth factor-β (TGF-β), the most potent fibrogenic cytokine for HSCs, which classically activates Smad signaling, and p38 MAPK signaling have been shown to influence collagen gene expression; however, the relative contribution and mechanisms that these two signaling pathways have in regulating collagen gene expression have not been investigated. The aim of this study was to investigate the relative roles and mechanisms of both Smad and p38 MAPK signaling in α1(I) collagen gene expression in HSCs. Inhibiting either p38 MAPK or Smad signaling reduced α1(I) collagen mRNA expression in untreated or TGF-β-treated HSCs, and when both signaling pathways were simultaneously inhibited, α1(I) collagen gene expression was essentially blocked. Both signaling pathways were found to independently and additively increase α1(I) collagen gene expression by transcriptional mechanisms. TGF-β treatment increased α1(I) collagen mRNA half-life, mediated by increased stability of α1(I) collagen mRNA through p38 MAPK signaling but not through Smad signaling. In conclusion, both p38 MAPK and Smad signaling independently and additively regulate α1(I) collagen gene expression by transcriptional activation, whereas p38 MAPK and not Smad signaling increased α1(I) collagen mRNA stability. Liver fibrosis represents a wound-healing process in response to a variety of chronic stimuli. Fibrosis is characterized by an excessive deposition of extracellular matrix proteins, of which type I collagen predominates. The activated hepatic stellate cell (HSC) 1The abbreviations used are: HSC, hepatic stellate cell; TGF-β, transforming growth factor-β; MAPK, mitogen-activated protein kinase; HA, hemagglutinin; ERK, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GFP, green fluorescent protein; FBS, fetal bovine serum; m.o.i., multiplicity of infection; SMA, smooth muscle α-actin; MEK, MAPK/ERK kinase. is the predominant cell type in the liver responsible for the increased synthesis and deposition of type I collagen during liver fibrosis. The HSCs normally reside in the liver in a quiescent state; however, following a fibrogenic stimulus, HSCs undergo a complex activation process in which the cell changes from a quiescent vitamin A-storing cell to an activated myofibroblast-like cell, which proliferates and becomes fibrogenic (1Friedman S.L. J. Biol. Chem. 2000; 275: 2247-2250Abstract Full Text Full Text PDF PubMed Scopus (1895) Google Scholar, 2Eng F.J. Friedman S.L. Am. J. Physiol. 2000; 279: G7-G11Crossref PubMed Google Scholar). An increase in DNA synthesis and cell proliferation occurs with HSC activation. Altered collagen synthesis, at both mRNA and protein levels, is observed with a dramatic increase in type I collagen along with smaller but significant increases in type III collagen (3Maher J.J. Bissell D.M. Friedman S.L. Roll F.J. J. Clin. Investig. 1988; 82: 450-459Crossref PubMed Scopus (131) Google Scholar, 4Friedman S.L. Rocky D.C. McGuire R.F. Maher J.J. Boyles J.K. Yamasaki G. Hepatology. 1992; 15: 234-243Crossref PubMed Scopus (244) Google Scholar, 5Knittel T. Schuppan D. Meyer zum Buschenfelde K.H. Ramadori G. Gastroenterology. 1992; 102: 1724-1735Abstract Full Text PDF PubMed Google Scholar). Transforming growth factor-β (TGF-β), the most potent profibrogenic cytokine for activated HSCs (6Friedman S.L. Semin. Liver Dis. 1999; 19: 129-140Crossref PubMed Scopus (351) Google Scholar), classically transmits intracellular signaling via Smad proteins (7Heldin C.H. Miyazono K. ten Dijke P. Nature. 1997; 390: 465-471Crossref PubMed Scopus (3358) Google Scholar). TGF-β binds to the constitutively active type II receptor, which then recruits and phosphorylates the type I receptor. Smad2 and Smad3 are recruited to the activated type I receptor where Smad2 and Smad3 are phosphorylated (8Piek E. Westermark U. Kastemar M. Heldin C.H. van Zoelen E.J. Nister M. ten Dijke P. Int. J. Cancer. 1999; 80: 756-763Crossref PubMed Scopus (74) Google Scholar, 9Massague J. Annu. Rev. Biochem. 1998; 67: 753-791Crossref PubMed Scopus (3999) Google Scholar). These then form a heterooligomeric complex with Smad4, and the complex translocates into the nucleus and regulates transcription of target genes. Smad7, an inhibitor of Smad signaling, associates with the activated type I receptor and interferes with Smad2 and Smad3 interaction with the receptor effectively inhibiting Smad2 and Smad3 phosphorylation and subsequent downstream signaling events (10Nakao A. Afrakhte M. Moren A. Nakayama T. Christian J.L. Heuchel R. Itoh S. Kawabata M. Heldin N.E. Heldin C.H. ten Dijke P. Nature. 1997; 389: 631-635Crossref PubMed Scopus (1572) Google Scholar, 11Hayashi H. Abdollah S. Qiu Y. Cai J. Xu Y.Y. Grinnell B.W. Richardson M.A. Topper J.N. Gimbrone Jr., M.A. Wrana J.L. Falb D. Cell. 1997; 89: 1165-1173Abstract Full Text Full Text PDF PubMed Scopus (1169) Google Scholar, 12Imamura T. Takase M. Nishihara A. Oeda E. Hanai J. Kawabata M. Miyazono K. Nature. 1997; 389: 622-626Crossref PubMed Scopus (873) Google Scholar). It has been shown that overexpression of Smad7 could effectively inhibit fibrogenesis. Gene transfer of Smad7 prevented bleomycin-induced lung fibrosis in mice considerably by intratracheal injection of a recombinant adenovirus containing Smad7 cDNA (13Nakao A. Fujii M. Matsumura R. Kumano K. Saito Y. Miyazono K. Iwamoto I. J. Clin. Investig. 1999; 104: 5-11Crossref PubMed Scopus (388) Google Scholar). In addition, gene transfer of Smad7 into unilateral ureteral obstruction-induced renal fibrosis in rats significantly prevented the accumulation of extracellular matrix proteins (14Terada Y. Hanada S. Nakao A. M. S. Int. Full Text Full Text PDF Scopus Google Scholar). of TGF-β signaling by Smad7 overexpression HSCs and fibrosis by in S. J. K. E. J. ten Dijke P. Gastroenterology. Full Text Full Text PDF PubMed Scopus Google Scholar). of the mitogen-activated protein extracellular signal-regulated c-Jun N-terminal protein and p38 MAPK that by growth and Biol. 1997; PubMed Scopus Google Scholar). TGF-β the activation of the p38 MAPK mediated by the a of the MAPK K. K. H. K. I. T. E. K. PubMed Scopus Google Scholar, H. J. M. J. H. K. E. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). and the MAPK are to of p38 MAPK, but the expression and the roles of and in cell is for p38 MAPK activation in M. U. S. A. 1999; PubMed Scopus Google Scholar), whereas is an of p38 MAPK in to T. T. Y. A. K. E. M. K. E. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). p38 MAPK signaling has been in signaling and collagen gene expression Am. J. Physiol. PubMed Scopus Google Scholar, K. S. Y. K. Y. H. M. T. Y. M. J. K. Hepatology. PubMed Scopus Google Scholar). In HSCs from Smad3 mice α1(I) mRNA were reduced in HSCs from mice Hepatology. PubMed Scopus Google Scholar). HSCs with reduced α1(I) collagen mRNA expression in HSCs S. J. K. E. J. ten Dijke P. Gastroenterology. Full Text Full Text PDF PubMed Scopus Google Scholar). both Smad and p38 MAPK signaling pathways have been shown to influence collagen gene the relative contribution and mechanisms these two signaling pathways have in regulating collagen gene expression are the of both and in the HSC to the study to the of Smad and p38 MAPK signaling α1(I) collagen gene expression in HSCs. found that of either p38 MAPK or Smad signaling pathways and expression of the α1(I) collagen mRNA to when both signaling pathways were inhibited, α1(I) collagen expression was essentially blocked. In addition, both and were shown to p38 MAPK, which is with collagen gene expression in HSCs. HSCs from mice either p38 MAPK or signaling pathways expression to that both p38 MAPK and Smad signaling increased transcriptional of the α1(I) collagen was found to mediated by p38 MAPK signaling, but not Smad signaling, where p38 MAPK signaling increased the stability of α1(I) collagen mRNA in untreated activated HSCs. TGF-β treatment increased α1(I) collagen mRNA that was mediated by p38 MAPK signaling and not by Smad signaling. that expression of the α1(I) collagen gene in HSCs is independently and by both p38 MAPK and Smad signaling in both untreated and TGF-β-treated HSCs by both transcriptional and mechanisms. and were by in of the liver with and by from rats or mice G. Hepatology. Google Scholar, Y. A. A. S. M. Hepatology. PubMed Scopus Google Scholar). HSC by the of the by was and were in with fetal bovine and in a at was HSCs were with recombinant a p38 MAPK inhibitor a inhibitor of a potent inhibitor of TGF-β type I receptor or following a were the by the of and and are in with by the of of which the gene by the was used a this The a Smad7 The Smad7 cDNA was from Wrana for and into the transfer adenovirus form of and were from was in and by were by adenovirus HSCs were with or at a multiplicity of of for in containing with both and the were simultaneously an of for the was to growth containing HSCs were with and the were with protein and were the were at for and then to a the proteins were a were with to protein and The were for with in were with the following in in or for at by the for at or for at by the for at for at by the for at smooth muscle for at by the for at for at by the for at The were with at for with the and proteins were following the was from HSCs for and and were G. Hepatology. Google Scholar). were for α1(I) collagen Y. Am. J. Physiol. PubMed Google and glyceraldehyde-3-phosphate and with of HSC were were by and by expression in HSCs, HSCs were from mice and was and by were for to the of were to are TGF-β to of p38 MAPK and but the of TGF-β MAPK signaling, HSCs, for were for and then with TGF-β for were by for p38 MAPK, ERK, and activation TGF-β activation of both and p38 MAPK was observed and following TGF-β treatment in HSCs the activation was not observed following treatment of the with of p38 MAPK and the of a inhibitor of p38 MAPK p38 MAPK activation, HSCs were for and then for with of and with TGF-β for of p38 MAPK was by a activated p38 MAPK with p38 phosphorylation at of and but not at a of the of inhibiting an that activates with a HSCs were with of for and with TGF-β for Inhibiting with treatment with and with not inhibit TGF-β Smad and p38 MAPK in both Smad and p38 MAPK signaling pathways are activated following TGF-β to TGF-β the activation of these signaling pathways independently of or are activated by a Smad proteins for TGF-β signaling, the of inhibiting Smad signaling Smad and Smad in response to TGF-β in HSCs was investigated. inhibit cell signaling, HSCs were with of HSCs, in were with and the following were of HSCs with of Smad7 protein expression by the of HSCs with Smad2 phosphorylation was treatment and for at the of inhibiting Smad signaling by TGF-β HSCs, for were with and the following Smad2 phosphorylation was with TGF-β for TGF-β increased Smad2 phosphorylation with both and HSCs with significantly Smad2 phosphorylation with HSCs. investigate the of Smad signaling the activation of p38 MAPK, HSCs were with and with TGF-β for and the phosphorylation of p38 MAPK was by a of p38 MAPK was found to increased following TGF-β with both and HSCs Smad signaling with not or phosphorylation of p38 MAPK, that these two signaling pathways are from HSCs, for were with for and then with TGF-β for p38 MAPK phosphorylation was by the p38 MAPK not inhibit phosphorylation of Smad2 these that these two signaling pathways are from p38 MAPK or Smad α1(I) mRNA the of p38 MAPK and α1(I) collagen mRNA HSCs were for and then for with or the were with TGF-β for and was and then α1(I) collagen mRNA expression was TGF-β increased α1(I) collagen mRNA in quiescent HSCs and however, α1(I) collagen mRNA expression was not observed in HSCs for and Inhibiting p38 MAPK with α1(I) collagen mRNA expression by whereas inhibiting with α1(I) collagen mRNA expression and Inhibiting Smad signaling with reduced α1(I) collagen mRNA expression with HSCs with TGF-β of both p38 MAPK and Smad signaling reduced expression of α1(I) collagen mRNA by to that of TGF-β-treated of Smad signaling with α1(I) collagen mRNA in HSCs. HSCs, for were with of to inhibit Smad signaling. the following the were for with TGF-β or in with to the of was and used to α1(I) collagen mRNA to that of is was used a from is shown TGF-β of p38 MAPK or Smad α1(I) mRNA the of inhibiting Smad and p38 MAPK signaling α1(I) collagen gene HSCs were with with from to a of the containing was the were of α1(I) collagen which was in activated HSCs in Inhibiting Smad signaling with reduced of α1(I) collagen mRNA by whereas of p38 MAPK α1(I) collagen mRNA expression by both signaling pathways were simultaneously inhibited, α1(I) collagen mRNA expression was reduced with that these two signaling pathways are responsible for α1(I) collagen expression in the Both and of p38 MAPK and Gene through p38 MAPK in and are to and of p38 MAPK, in HSCs has not been roles in MAPK signaling, HSCs were with and with TGF-β for were and activation of p38 MAPK was by a p38 MAPK was by for expression of the the and proteins not either or p38 whereas with both and p38 phosphorylation These that both and are of p38 MAPK and MAPK signaling. the of Smad signaling in HSCs, a potent and inhibitor of TGF-β type I receptor was used to signaling E. A. S. J. J. R. J. PubMed Scopus Google Scholar). the of Smad2 activation, HSCs were for then for with of and with TGF-β for of Smad2 was by a activated TGF-β type I receptor with Smad2 phosphorylation at of phosphorylation of p38 MAPK and the of α1(I) collagen mRNA HSCs, in were with and with TGF-β for was and were reduced of α1(I) collagen mRNA by and inhibiting α1(I) collagen mRNA expression by which was at the when both and were both and roles in regulating α1(I) collagen gene expression through p38 however, signaling to have a Smad signaling with reduced α1(I) collagen mRNA expression by and inhibiting both Smad and a of both Smad and p38 α1(I) collagen mRNA expression by and of HSCs with reduced of α1(I) collagen mRNA by and inhibiting with α1(I) collagen mRNA expression by the both and by and Smad signaling with reduced α1(I) collagen mRNA expression by and inhibiting both Smad and by and Both p38 MAPK and Smad to the of in Smad and p38 MAPK signaling both regulate α1(I) collagen expression in HSCs, to these signaling pathways regulate smooth muscle a for HSC activation in the the roles of p38 MAPK and Smad signaling expression in HSCs, HSCs were with with were for with containing the p38 MAPK inhibitor of Smad signaling with significantly reduced the of expression by with whereas of p38 MAPK reduced expression by with HSCs expression was significantly reduced by with when both p38 MAPK and Smad signaling pathways were These a for both Smad and p38 MAPK signaling in HSC activation. Both p38 MAPK and Smad of the α1(I) Gene HSC p38 MAPK and Smad signaling both regulate α1(I) collagen gene expression to investigate the by which these signaling pathways this a transcriptional for these signaling HSCs were from mice the Y. A. A. S. M. Hepatology. PubMed Scopus Google Scholar, K. D. K. A. A. M. Gene 1999; Google Scholar). α1(I) collagen gene has been shown to to that of the α1(I) collagen gene following HSC activation Y. A. A. S. M. Hepatology. PubMed Scopus Google Scholar). HSCs were for and the were with from to with expression was and by Inhibiting either p38 MAPK or Smad signaling expression in expression in HSCs with was reduced with untreated whereas reduced expression with untreated the that p38 MAPK and Smad signaling both influence transcriptional of the α1(I) collagen p38 MAPK but Smad α1(I) mRNA in of the α1(I) collagen mRNA has been shown to following HSC activation M. M. S. Cell. Biol. 1997; PubMed Google Scholar). the contribution that both p38 MAPK and Smad signaling have in α1(I) collagen p38 MAPK was with for from to or Smad signaling was with in transcription was with was from the or following treatment and was to The of α1(I) collagen mRNA were and to that of In HSCs, the of α1(I) collagen mRNA has been to in quiescent HSCs, the is to M. M. S. Cell. Biol. 1997; PubMed Google Scholar). In HSCs for found the of α1(I) collagen mRNA to and p38 MAPK was with the of α1(I) collagen mRNA was reduced to that p38 MAPK α1(I) collagen mRNA and the of Smad signaling not the of α1(I) collagen mRNA and The in α1(I) collagen mRNA stability following of p38 MAPK was not by cell cell was not by treatment of the with not These that p38 MAPK signaling α1(I) collagen whereas Smad signaling not influence α1(I) collagen mRNA TGF-β of the α1(I) mRNA by p38 MAPK but Smad has been to increase α1(I) collagen mRNA at in by gene transcription J. Cell. Biochem. PubMed Scopus Google Scholar). a for TGF-β in α1(I) collagen mRNA in the HSC has not been investigated. the of TGF-β α1(I) collagen mRNA stability by HSCs, in with or the following HSCs, in were with to a treatment with The of α1(I) collagen mRNA in was of p38 MAPK signaling the stability of α1(I) collagen mRNA to of the with TGF-β significantly increased the of α1(I) collagen mRNA to with stability of α1(I) collagen mRNA was to the of the following treatment with that p38 MAPK signaling is responsible for the increased stability of the α1(I) collagen mRNA the of Smad signaling not the of α1(I) collagen mRNA in untreated or HSCs these that TGF-β increases the stability of α1(I) collagen mRNA that is mediated by p38 MAPK and not by Smad signaling. TGF-β is the most potent profibrogenic cytokine for activated HSCs. TGF-β classically intracellular signaling via Smad is by to the constitutively active type II receptor, which then recruits and phosphorylates the type I receptor. The activated type I receptor associates with and phosphorylates Smad2 and Smad3 (8Piek E. Westermark U. Kastemar M. Heldin C.H. van Zoelen E.J. Nister M. ten Dijke P. Int. J. Cancer. 1999; 80: 756-763Crossref PubMed Scopus (74) Google Scholar, 9Massague J. Annu. Rev. Biochem. 1998; 67: 753-791Crossref PubMed Scopus (3999) Google Scholar), which then an complex with complex translocates into the nucleus and binds to regulating transcription of target genes. Smad7 a complex with activated type I receptor and effectively Smad2 and Smad3 interaction with the receptor and subsequent downstream signaling (10Nakao A. Afrakhte M. Moren A. Nakayama T. Christian J.L. Heuchel R. Itoh S. Kawabata M. Heldin N.E. Heldin C.H. ten Dijke P. Nature. 1997; 389: 631-635Crossref PubMed Scopus (1572) Google Scholar, 11Hayashi H. Abdollah S. Qiu Y. Cai J. Xu Y.Y. Grinnell B.W. Richardson M.A. Topper J.N. Gimbrone Jr., M.A. Wrana J.L. Falb D. Cell. 1997; 89: 1165-1173Abstract Full Text Full Text PDF PubMed Scopus (1169) Google Scholar, 12Imamura T. Takase M. Nishihara A. Oeda E. Hanai J. Kawabata M. Miyazono K. Nature. 1997; 389: 622-626Crossref PubMed Scopus (873) Google Scholar). Smad7 is an inhibitor for TGF-β signaling, and (13Nakao A. Fujii M. Matsumura R. Kumano K. Saito Y. Miyazono K. Iwamoto I. J. Clin. Investig. 1999; 104: 5-11Crossref PubMed Scopus (388) Google Scholar, Y. Hanada S. Nakao A. M. S. Int. Full Text Full Text PDF Scopus Google Scholar, S. J. K. E. J. ten Dijke P. Gastroenterology. Full Text Full Text PDF PubMed Scopus Google have Smad7 a for regulating in of fibrosis. of α1(I) collagen mRNA is but not in HSCs from both Smad3 mice Am. J. Physiol. PubMed Scopus Google and in HSCs with S. J. K. E. J. ten Dijke P. Gastroenterology. Full Text Full Text PDF PubMed Scopus Google Scholar), signaling pathways to collagen gene expression in and p38 MAPK signaling has been in TGF-β and in α1(I) collagen gene expression Am. J. Physiol. PubMed Scopus Google Scholar, K. S. Y. K. Y. H. M. T. Y. M. J. K. Hepatology. PubMed Scopus Google Scholar). the relative contribution of these two signaling pathways and the mechanisms by which regulate collagen gene expression in HSCs have not been investigated. In this the relative contribution of p38 MAPK and Smad signaling in regulating α1(I) collagen gene expression in HSCs. that inhibiting either p38 MAPK or Smad signaling α1(I) collagen mRNA in and HSCs It is that of p38 MAPK signaling with could inhibit phosphorylation of the TGF-β type I receptor and subsequent phosphorylation of Smad2 and to in the TGF-β type I receptor and p38 MAPK E. A. S. J. J. R. J. PubMed Scopus Google Scholar). that not inhibit Smad2 phosphorylation that this not Smad signaling and is an to investigate the of p38 MAPK in cell signaling. that Smad7 in HSCs and treatment of HSCs with by inhibiting Smad2 and p38 MAPK and In addition, found that expression of α1(I) collagen mRNA was when both Smad and p38 MAPK signaling pathways were and that both p38 MAPK and Smad signaling independently and additively regulate the α1(I) collagen gene in both untreated and TGF-β-treated HSCs, and that these two signaling pathways the two signaling pathways responsible for regulating α1(I) collagen gene expression in the MAPK pathways simultaneously by the MAPK J. Physiol. Rev. PubMed Scopus Google Scholar). and are to for p38 MAPK signaling, roles are the cell is the for p38 MAPK in the mice M. H. M. PubMed Scopus Google Scholar), whereas activation of is for p38 MAPK activation in R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The roles of and in HSCs have not been In this and were by with to investigate and are the of p38 MAPK in HSCs. Inhibiting both and effectively phosphorylation of p38 MAPK and reduced α1(I) collagen gene expression in both untreated and TGF-β-treated HSCs The at which α1(I) collagen gene expression was reduced was to that when p38 MAPK signaling was These that both and are and roles for p38 MAPK in HSCs. the roles of Smad in HSCs, signaling was a potent and inhibitor of TGF-β type I receptor E. A. S. J. J. R. J. PubMed Scopus Google Scholar). was found to inhibit α1(I) collagen mRNA expression in both untreated and TGF-β-treated HSCs, and when both Smad and signaling pathways were simultaneously inhibited, α1(I) collagen mRNA expression was that both and collagen gene expression are essentially by both p38 MAPK and Smad signaling. muscle is a of HSC activation. that both p38 MAPK and Smad signaling independently regulate expression in untreated HSCs that both p38 MAPK and Smad signaling to HSC however, of expression inhibiting both p38 MAPK and Smad signaling, signaling pathways are of is with changes in HSCs. in HSCs are and in the HSCs, both with and with in and into myofibroblast-like In HSCs with or with are smaller and in not however, in to that TGF-β signaling with Smad7 not expression in activated and in S. J. K. E. J. ten Dijke P. Gastroenterology. Full Text Full Text PDF PubMed Scopus Google Scholar). the are with that of TGF-β signaling in HSCs in when with an adenovirus a TGF-β type II receptor reduced expression I. G. M. H. M. K. H. H. S. J. Full Text Full Text PDF PubMed Scopus Google Scholar). It is that the activated HSC is responsible for the increase in collagen gene The mechanisms responsible for regulating the α1(I) collagen gene in HSCs are collagen expression following HSC activation has been shown to mediated by both an increase in gene transcription and an increase in the stability of the α1(I) collagen mRNA Hepatology. PubMed Scopus Google Scholar, Y. A. A. S. M. Hepatology. PubMed Scopus Google Scholar, K. D. K. A. A. M. Gene 1999; Google Scholar). investigate the mechanisms of p38 MAPK and Smad signaling regulate the α1(I) collagen the transcriptional and were In to a of p38 MAPK and Smad signaling collagen gene HSCs were from mice the K. D. K. A. A. M. 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PubMed Scopus Google and in stellate A. M. K. Y. A. T. J. PubMed Scopus Google Scholar), and this of p38 MAPK α1(I) collagen mRNA stability. that in HSCs TGF-β increases α1(I) collagen mRNA stability through p38 MAPK signaling and not by a In both p38 MAPK and Smad signaling independently regulate α1(I) collagen gene in HSCs in an transcription is activated by both Smad and p38 MAPK signaling whereas the stability of α1(I) collagen mRNA is mediated by p38 MAPK signaling, but not by Smad signaling. In addition, found that increases α1(I) collagen mRNA which was mediated by p38 MAPK
Tsukada et al. (Thu,) studied this question.