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Published 3 January 2005. doi:10.1083/jcb.200404146
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 168, Number 1, 55-66
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Article

p107 inhibits G1 to S phase progression by down-regulating expression of the F-box protein Skp2



Geneviève Rodier1, Constantin Makris1,2, Philippe Coulombe1,3, Anthony Scime4, Keiko Nakayama5, Keiichi I. Nakayama5, and Sylvain Meloche1,2,3

1 Institut de recherche en immunovirologie et cancérologie, Université de Montréal, Montreal, Quebec H3C 3J7, Canada
2 Department of Pharmacology, Université de Montréal, Montreal, Quebec H3C 3J7, Canada
3 Department of Molecular Biology, Université de Montréal, Montreal, Quebec H3C 3J7, Canada
4 Ottawa Health Research Institute, Ottawa, Ontario K1Y 4E9, Canada
5 Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan

Correspondence to Sylvain Meloche: sylvain.meloche{at}umontreal.ca

Cell cycle progression is negatively regulated by the pocket proteins pRb, p107, and p130. However, the mechanisms responsible for this inhibition are not fully understood. Here, we show that overexpression of p107 in fibroblasts inhibits Cdk2 activation and delays S phase entry. The inhibition of Cdk2 activity is correlated with the accumulation of p27, consequent to a decreased degradation of the protein, with no change of Thr187 phosphorylation. Instead, we observed a marked decrease in the abundance of the F-box receptor Skp2 in p107-overexpressing cells. Reciprocally, Skp2 accumulates to higher levels in p107–/– embryonic fibroblasts. Ectopic expression of Skp2 restores p27 down-regulation and DNA synthesis to the levels observed in parental cells, whereas inactivation of Skp2 abrogates the inhibitory effect of p107 on S phase entry. We further show that the serum-dependent increase in Skp2 half-life observed during G1 progression is impaired in cells overexpressing p107. We propose that p107, in addition to its interaction with E2F, inhibits cell proliferation through the control of Skp2 expression and the resulting stabilization of p27.

Constantin Makris's present address is Merck Frosst Center for Therapeutic Research, Kirkland, Quebec H9H 3L1, Canada.

Abbreviations used in this paper: APC/C, anaphase-promoting complex/cyclosome; MEF, mouse embryonic fibroblast; siRNA, small interfering RNA.


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