CHIP controls the sensitivity of transforming growth factor-β signaling by modulating the basal level of Smad3 through ubiquitin-mediated degradation

Hong Xin, Xialian Xu, Linyu Li, Hongxiu Ning, Yu Rong, Yu Shang, Yinyin Wang, Xin Yuan Fu, Zhijie Chang

Research output: Contribution to journalArticle

70 Scopus citations

Abstract

Transforming growth factor-β (TGF-β) signaling is critical in a variety of biological processes such as cell proliferation, differentiation, and apoptosis. TGF-β signaling is mediated by a group of proteins including TGF-β receptors and Smads. It is known that different cells can exhibit different sensitivities to TGF-β. Several molecular mechanisms, such as the differential expression of the receptor levels, have been suggested as contributing to these differences. Here, we report evidence for a novel mechanism of regulating TGF-β sensitivity that depends on the role of CHIP (carboxyl terminus of Hsc70-interacting protein) in regulating the basal level of Smad3 via the ubiquitin-dependent degradation pathway. First, using a luciferase assay we found that overexpression of CHIP inhibited TGF-β signaling, whereas silencing CHIP expression by small interfering RNAs led to increased TGF-β signaling sensitivity. Second, based on the results of cell proliferation assays and JunB expression, we found that TGF-β signaling could be abolished by stably overexpressing CHIP. Third, in those cell lines with stably expressed CHIP, we observed that the Smad3 protein level was dramatically decreased. Finally, we demonstrated that CHIP served as a U-box dependent E3 ligase that can directly mediate ubiquitination and degradation of Smad3 and that this action of CHIP was independent of TGF-β signaling. Taken together, these findings suggest that CHIP can modulate the sensitivity of the TGF-β signaling by controlling the basal level of Smad3 through ubiquitin-mediated degradation.

Original languageEnglish (US)
Pages (from-to)20842-20850
Number of pages9
JournalJournal of Biological Chemistry
Volume280
Issue number21
DOIs
StatePublished - May 27 2005

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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