Transcriptional Regulation of Type I Collagen Gene Expression by Transforming Growth Factor-β/Smad Signaling and Its Antagonistic Factors

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概要

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• Increased production of type I collagen is a common hallmark of fibrotic diseases in various organs including the liver. This increase is exerted mainly by the transcriptional upregulation of the genes coding for the al and α2 chains of type I collagen, and transforming growth factor-β (TGF-β) is known to be a key player in stimulating gene transcription. We have previously shown that the -313 to -183 upstream sequence of α2(I) collagen gene (COL1A2) is essential for basal and TGF-β-stimulated transcription in skin fibroblasts and hepatic stellate cells, the major source of collagen in the liver. We therefore designated this region the TGF-β-responsive element (TbRE), and revealed that a ubiquitous trans-activator SpI and unknown co-factor(s) bind to this region to mediate the stimulatory effect of TGF-β. Recently Smad3, an intracellular mediator of the TGF-2 signal transduction pathway, was shown to bind to the TbRE, and its interaction with SpI has been implicated in TGF-β-elicited COL1A2 stimulation. We have demonstrated ligand-independent phosphorylation and constitutive nuclear localization of Smad3 in an activated hepatic stellate cell clone. Experiments using transgenic mice harboring the COL1A2 upstream sequence indicated that the COL1A2 promoter is activated in a cell type-specific manner during hepatic fibrogenesis. We have recently revealed that interactions between GC box binding factors (Sp1/Sp3) and Smad proteins modulate cell type-specific COL1A2 transcription in the liver. Several factors have been shown to antagonize the TGF-β/Smad stimulation of COL1A2 transcription, which may contribute to the development of new therapeutic means for organ fibrosis.

• 日本結合組織学会の論文
• 2002-06-25

著者

• Nakao Atsuhito

  Allergy Research Center Juntendo University School Of Medicine

• Inagaki Y

  Liver Fibrosis Research Unit Department Of Community Health Tokai University School Of Medicine

• Inagaki Yutaka

  Department Of Internal Medicine And The Division Of Clinical Research National Kanazawa Hospital

• Inagaki Yutaka

  Department Of Community Health Division Of Community And Environmental Health Tokai University Schoo

• NEMOTO Tomoyuki

  Department of Internal Medicine, Kanazawa Red Cross Hospital

• Nemoto T

  Department Of Functional Biology Graduate School Of Biostudies Kyoto University

• Nemoto Tomoyuki

  Department Of Basic Sciences Faculty Of Science And Engineering Ishinomaki Senshu University

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