p45SKP2 promotes p27Kip1 degradation and induces S phase in quiescent cells.
The F-box protein p45SKP2 is the substrate-targeting subunit of the ubiquitin-protein ligase SCFSKP2 and is frequently overexpressed in transformed cells. Here we report that expression of p45SKP2 in untransformed fibroblasts activates DNA synthesis in cells that would otherwise growth-arrest. Expression of p45SKP2 in quiescent fibroblasts promotes p27Kip1 degradation, allows the generation of cyclin-A-dependent kinase activity and induces S phase. Coexpression of a degradation-resistant p27Kip1 mutant suppresses p45SKP2-induced cyclin-A-kinase activation and S-phase entry. We propose that p45SKP2 is important in the progression from quiescence to S phase and that the ability of p45SKP2 to promote p27Kip1 degradation is a key aspect of its S-phase-inducing function. In transformed cells, p45SKP2 may contribute to deregulated initiation of DNA replication by interfering with p27Kip1 function.
Sutterlüty
H
H
Friedrich Miescher Institut, Basel, Switzerland.
Chatelain
E
E
Marti
A
A
Wirbelauer
C
C
Senften
M
M
Müller
U
U
Krek
W
W
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001665:Binding Sites; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D016895:Culture Media, Serum-Free; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004261:DNA Replication; D015870:Gene Expression; D006801:Humans; D007399:Interphase / Q000502:physiology; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D009154:Mutation; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D016196:S Phase / Q000502:physiology*; D044786:S-Phase Kinase-Associated Proteins; D025521:Tumor Suppressor Proteins
C493962:Cdkn1b protein, rat; D018797:Cell Cycle Proteins; D016895:Culture Media, Serum-Free; D008869:Microtubule-Associated Proteins; D011994:Recombinant Proteins; D044786:S-Phase Kinase-Associated Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases