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 language | English |
|---|---|
| Pages (from-to) | 55-66 |
| Number of pages | 12 |
| Journal | Journal of Cell Biology |
| Volume | 168 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Jan 3 2005 |
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All Science Journal Classification (ASJC) codes
- Cell Biology
Cite this
p107 inhibits G1 to S phase progression by down-regulating expression of the F-box protein Skp2. / Rodier, Geneviève; Makris, Constantin; Coulombe, Philippe; Scime, Anthony; Nakayama, Keiko; Nakayama, Keiichi I.; Meloche, Sylvain.
In: Journal of Cell Biology, Vol. 168, No. 1, 03.01.2005, p. 55-66.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - p107 inhibits G1 to S phase progression by down-regulating expression of the F-box protein Skp2
AU - Rodier, Geneviève
AU - Makris, Constantin
AU - Coulombe, Philippe
AU - Scime, Anthony
AU - Nakayama, Keiko
AU - Nakayama, Keiichi I.
AU - Meloche, Sylvain
PY - 2005/1/3
Y1 - 2005/1/3
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=12144264298&partnerID=8YFLogxK
U2 - 10.1083/jcb.200404146
DO - 10.1083/jcb.200404146
M3 - Article
C2 - 15631990
AN - SCOPUS:12144264298
VL - 168
SP - 55
EP - 66
JO - Journal of Cell Biology
JF - Journal of Cell Biology
SN - 0021-9525
IS - 1
ER -