期刊
ONCOGENE
卷 23, 期 5, 页码 1064-1075出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1207204
关键词
Skp2; p27(Kip1); TGF-beta; protein degradation; ubiquitin; Cdc34 and Cks1
资金
- NCI NIH HHS [CA95527-01, R01 CA095527] Funding Source: Medline
- NIA NIH HHS [R01 AG011085] Funding Source: Medline
TGF-beta is a multifunctional growth factor whose best-known function is to inhibit cell growth and suppress tumor formation. TGF-beta causes cells to accumulate in mid-to-late G1 phase by blocking the transition from G1 to S. It has been shown that TGF-beta inhibits Cdk2-cyclin E kinase activity by promoting the binding of cell cycle inhibitor p27(Kip1) to the kinase complexes. Here, we show that TGF-beta treatment leads to stabilization of p27(Kip1) during G1 to S transition. We found that TGF-beta negatively regulates components of the SCF complex, which degrades the p27(Kip1) during the G1 to S transition, through two distinct mechanisms. Using a pulse-chase analysis, we demonstrated that the stability of Skp2 decreases in the presence of TGF-beta. Destabilization of Skp2 by ubiquitin-mediated proteolysis was also demonstrated that in an in vitro degradation system, using cell extracts prepared from TGF-beta-treated cultured cells. In addition, TGF-beta treatment decreases the levels of Cks1 mRNA. The deficiency of Cks1 in TGF-beta-treated cells likely contributes to the stabilization of p27(Kip1) and destabilization of Skp2, because in the absence of Cks1, SCFSkp2 cannot ubiquitinate p27(Kip1); instead, self-ubiquitination of Skp2 occurs. Thus, stabilization of the cell cycle inhibitor p27(Kip1) and cell growth inhibition in response to TGF-beta occur in part through limiting the threshold of the SCFSkp2 ubiquitin ligase by transcriptional and post-transcriptional mechanisms.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据