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Molecular and Cellular Biology, April 2007, p. 2967-2979, Vol. 27, No. 8
0270-7306/07/$08.00+0     doi:10.1128/MCB.01830-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Cdh1-Anaphase-Promoting Complex Targets Skp2 for Destruction in Transforming Growth Factor ß-Induced Growth Inhibition{triangledown} ,{dagger}

Weijun Liu,1,2 George Wu,1 Wenqi Li,1,2 David Lobur,1 and Yong Wan1,2*

University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213,1 Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania2

Received 27 September 2006/ Returned for modification 17 November 2006/ Accepted 22 January 2007

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 ß (TGF-ß) 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-ß-induced cell cycle arrest, as does expression of a nondegradable Skp2 mutant. Furthermore, we demonstrate that TGF-ß-induced Skp2 degradation is mediated by the Smad cascade. The degradation of Skp2 stabilizes p27, thereby ensuring TGF-ß-induced cell cycle arrest. These results identify a novel mechanism for tumor suppression by TGF-ß and explain why dysfunction of APC in the TGF-ß pathway in responsive cells is associated with cancer.

* Corresponding author. Mailing address: University of Pittsburgh Cancer Institute, Hillman Cancer Center, Suite 2.6C, 5117 Centre Avenue, Pittsburgh, PA 15213. Phone: (412) 623-3275. Fax: (412) 623-7761. E-mail: yow4{at}pitt.edu

{triangledown} Published ahead of print on 5 February 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, April 2007, p. 2967-2979, Vol. 27, No. 8
0270-7306/07/$08.00+0     doi:10.1128/MCB.01830-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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