Abstract
The inhibition of cyclin-dependent kinase activity by p27 contributes to regulation of cell cycle progression. Serine 10 is the major phosphorylation site of p27, and its phosphorylation has been shown to affect the stability and nuclear export of p27 at the G0-G1 transition in transfected cultured cells. To investigate the physiological relevance of p27 phosphorylation on Ser10, we generated p27 "knock-in" mice that harbor an S10A mutation in this protein. Mice homozygous for the mutation (p27(S10A/S10A) mice) were normal in body size, but the abundance of p27 was decreased in many organs, including brain, thymus, spleen, and testis. The stability of p27 in G0 phase was markedly reduced in lymphocytes of p27(S10A/S10A) mice compared with that in wild-type cells, whereas p27 stability in S phase was similar in cells of the two genotypes. The degradation of p27 in cells of the mutant mice at G0 phase was prevented by a proteasome inhibitor. These data indicate that the physiological role of p27 phosphorylation on Ser10 is to stabilize the protein in G0 phase. Unexpectedly, the nuclear export of p27 at the G0-G1 transition occurred normally in p27(S10A/S10A) mouse embryonic fibroblasts, indicating that phosphorylation of Ser10 is dispensable for this process.
Highlights
Progression of the cell cycle in eukaryotic cells is regulated by a series of protein complexes composed of cyclins and cyclindependent kinases (CDKs),1 the activity of which is in turn controlled by a group of CDK inhibitors (CKIs) [1, 2]
The protein is phosphorylated on Thr187 by the cyclin E-CDK2 complex [18, 19], and the phosphorylation of this residue is required for binding of p27 to Skp2, an F-box protein that is thought to function as the receptor component of an SCF ubiquitin ligase complex; such binding results in the ubiquitylation and degradation of p27 (20 –25)
Regulation of the cell cycle at the G1-S boundary is thought to be important for the control of cell proliferation
Summary
Progression of the cell cycle in eukaryotic cells is regulated by a series of protein complexes composed of cyclins and cyclindependent kinases (CDKs),1 the activity of which is in turn controlled by a group of CDK inhibitors (CKIs) [1, 2]. We show that the stability of the mutant protein is markedly reduced in certain cell types of p27S10A/S10A mice at G0 phase.
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