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刘成海

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Smads 2 and 3 Are Differentially Activated by Transforming Growth Factor-β (TGF-β) in Quiescent and Activated Hepatic Stellate Cells

刘成海Chenghai Liu Marianna D. A. Gaca E. Scott Swenson Vincent F. Vellucci Michael Reiss Rebecca G. Wells

The Journal of Biological Chemstry Vol. 278, No. 13, Issue of March 28, pp. 11721-11728, 2003,-0001,():

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摘要/描述

Hepatic stellate cells are the primary cell type responsible for matrix deposition in liver fibrosis, undergoing a process of transdifferentiation into fibrogenic myofibroblasts. These cells, which undergo a similar transdifferentiation process when cultured in vitro, are a major target of the profibrogenic agent transforming growth factor-β (TGF-β). We have studied activation of the TGF-β downstream signaling molecules Smads 2, 3, and 4 in hepatic stellate cells (HSC) cultured in vitro for 1, 4, and 7 days, with quiescent, intermediate, and fully transdifferentiated phenotypes, respectively. Total levels of Smad4, common to multiple TGF-β superfamily signaling pathways, do not change as HSC transdifferentiate, and the protein is found in both nucleus and cytoplasm, independent of treatment with TGF-β or the nuclear export inhibitor leptomycin B. TGF-β mediates activation of Smad2 primarily in early cultured cells and that of Smad3 primarily in transdifferentiated cells. The linker protein SARA, which is required for Smad2 signaling, disappears with transdifferentiation. Additionally, day 7 cells demonstrate constitutive phosphorylation and nuclear localization of Smad 2, which is not affected by pretreatment with TGF-β- neutralizing antibodies, a type I TGF-β receptor kinase inhibitor, or activin- neutralizing antibodies. These results demonstrate essential differences between TGF-β-mediated signaling pathways in quiescent and in vitro transdifferentiated hepatic stellate cells.

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版权说明:以下全部内容由刘成海上传于   2007年05月08日 10时36分06秒,版权归本人所有。

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