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MBC in Press, published online ahead of print January 10, 2007
Mol. Biol. Cell 10.1091/mbc.E06-09-0809

A more recent version of this article appeared on March 1, 2007
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Submitted on September 11, 2006
Revised on December 13, 2006
Accepted on January 2, 2007

The Anaphase-promoting Complex Coordinates the Initiation of Lens Differentiation

George Wu,*{dagger} Sara Glickstein,{dagger} Weijun Liu,*{ddagger} Takeo Fujita,*{ddagger} Wenqi Li,*{ddagger} Qi Yang,* Robert Duvoisin,{sect} and Yong Wan*{ddagger}

*University of Pittsburgh Cancer Institute, Pittsburgh, PA 15312; {ddagger}Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; {dagger}Weill Medical College of Cornell University, New York, NY 10021; {sect}Neurological Sciences Institute, Oregon Health & Science University, Beaverton, OR 97006

Monitoring Editor: Mark Solomon

Lens development requires the precise coordination of cell division and differentiation. The mechanisms by which the differentiation program is initiated following cell cycle arrest remains not well understood. Cyclin-dependent kinase inhibitors (CKIs), such as p15 and p21, have been suggested to be critical components that inhibit G1 progression and therefore, their activation is necessary for quiescence and important for the onset of differentiation. Regulation of p15 and p21 is principally governed by TGF-{beta} signaling pathway. We have identified that Cdh1/APC, a critical ubiquitin protein ligase, plays an important role in regulating lens differentiation by facilitating TGF-{beta} induced degradation of SnoN, a transcriptional corepressor that needs to be removed for transcriptional activation of p15 and p21. The depletion of Cdh1 by RNA interference attenuates the TGF-{beta}-mediated induction of p15 and p21 and significantly blocks lens differentiation. Expression of nondegradable SnoN also noticeably attenuates lens induction. Furthermore, we have shown that Cdh1 and SnoN form a complex at the onset of lens differentiation. In vivo histological analysis confirms our biochemical and genetic results. Thus, Cdh1/APC is crucial to the coordination of cell cycle progression and the initiation of lens differentiation through mediating TGF-{beta} signaling-induced destruction of SnoN.

Address correspondence to: Yong Wan (yow4{at}pitt.edu)




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