p107 inhibits G1 to S phase progression by down-regulating expression of the F-box protein Skp2.
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.
Rodier
Geneviève
G
Institut de recherche en immunovirologie et cancérologie, Université de Montréal, Montreal, Quebec H3C 3J7, Canada.
Makris
Constantin
C
Coulombe
Philippe
P
Scime
Anthony
A
Nakayama
Keiko
K
Nakayama
Keiichi I
KI
Meloche
Sylvain
S
D000818:Animals; D042846:CDC2-CDC28 Kinases / Q000378:metabolism; D002237:Carbohydrate Dehydrogenases / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D044842:Cullin Proteins / Q000378:metabolism; D016895:Culture Media, Serum-Free; D051357:Cyclin-Dependent Kinase 2; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000378:metabolism; D004789:Enzyme Activation; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D016193:G1 Phase / Q000502:physiology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D050720:Retinoblastoma-Like Protein p107; D016196:S Phase / Q000502:physiology*; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
C493961:Cdkn1b protein, mouse; C493962:Cdkn1b protein, rat; D018797:Cell Cycle Proteins; C100318:Cullin 1; D044842:Cullin Proteins; D016895:Culture Media, Serum-Free; D016213:Cyclins; D009687:Nuclear Proteins; C493844:RBL1 protein, human; D034741:RNA, Small Interfering; D050720:Retinoblastoma-Like Protein p107; D044786:S-Phase Kinase-Associated Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D002237:Carbohydrate Dehydrogenases; C019859:cellobiose-quinone oxidoreductase; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495893:Cdk2 protein, mouse; C495892:Cdk2 protein, rat; D051357:Cyclin-Dependent Kinase 2