p107 Skps from S phase

p107 Skps from S phase ocket proteins find multiple routes to stop cell proliferation, according to results on page 55 from Rodier et al. The well-known antiproliferative route taken by pocket proteins, including pRb and p107, is through interaction with E2F. When bound to pRb, E2F cannot initiate the transcription of cell cycle progression genes, and cells thus linger in G1. But pocket proteins are also able to block proliferation by less well-characterized E2Findependent pathways. The new results reveal that, for p107, this pathway operates by interfering with protein degradation. The end result is a low level of Cdk activity that prevents S phase. Serum addition or p107 deletion led to stabilization of high levels of Skp2, the substrate recognition component of an E3 ligase ubiquitination complex. The resulting complex could degrade the CDK inhibitor p27, leaving cells free to transition from G1 to S phase. In fibroblast cell lines overexpressing p107, however, Skp2 was destabilized, p27 was no longer degraded, and the cell cycle transition was blocked. Skp2 was shown to be degraded by two different pathways, but neither of these known pathways seems to be strongly affected by p107. Although some of p107’s effect on Skp2 abundance may be mediated by the anaphase-promoting complex, a third unidentified degradation pathway is probably also involved. The only pocket protein that is a proven tumor suppressor is pRb. pRb was also recently shown to inhibit Skp2 function (Ji et al. Mol. Cell. , 16:47–58), although through a different mechanism involving direct binding to Skp2. If the Skp2 effect is the tumor suppressor function of pRb, it is likely that p107 is also a tumor suppressor, whose loss is offset by other pocket proteins. P Overexpressed p107 (open boxes) makes Skp2 unstable.