Cdh1-anaphase-promoting complex targets Skp2 for destruction in transforming growth factor beta-induced growth inhibition.
As a subunit of a ubiquitin ligase, Skp2 is implicated in facilitating cell cycle progression via degradation of various protein targets. We report here that Skp2 is rapidly degraded following cellular stimulation by the cytokine transforming growth factor beta (TGF-beta) and that this degradation stabilizes the cell cycle arrest protein p27. The Skp2 degradation is mediated by Cdh1-anaphase-promoting complex (APC), as shown by depletion of Cdh1 with small interfering RNA, and by reconstitution of ubiquitylation reactions in a purified system. Blockage of Skp2 degradation greatly reduces TGF-beta-induced cell cycle arrest, as does expression of a nondegradable Skp2 mutant. Furthermore, we demonstrate that TGF-beta-induced Skp2 degradation is mediated by the Smad cascade. The degradation of Skp2 stabilizes p27, thereby ensuring TGF-beta-induced cell cycle arrest. These results identify a novel mechanism for tumor suppression by TGF-beta and explain why dysfunction of APC in the TGF-beta pathway in responsive cells is associated with cancer.
Liu
Weijun
W
University of Pittsburgh Cancer Institute, Hillman Cancer Center, Suite 2.6C, 5117 Centre Avenue, Pittsburgh, PA 15213, USA.
Wu
George
G
Li
Wenqi
W
Lobur
David
D
Wan
Yong
Y
D064173:Anaphase-Promoting Complex-Cyclosome; D048708:Cell Growth Processes / Q000187:drug effects; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D020868:Gene Silencing; D006801:Humans; D008954:Models, Biological; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D025801:Ubiquitin / Q000378:metabolism; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism*
D044786:S-Phase Kinase-Associated Proteins; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D025801:Ubiquitin; D050760:Cyclin-Dependent Kinase Inhibitor p27; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome