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

Geneviève Rodier, Constantin Makris, Philippe Coulombe, Anthony Scime, Keiko Nakayama, Keiichi I. Nakayama, Sylvain Meloche

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)55-66
Number of pages12
JournalJournal of Cell Biology
Volume168
Issue number1
DOIs
Publication statusPublished - Jan 3 2005

All Science Journal Classification (ASJC) codes

  • Cell Biology

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