Skp2-mediated degradation of p27 regulates progression into mitosis.
Although Skp2 has been thought to mediate the degradation of p27 at the G(1)-S transition, Skp2(-/-) cells exhibit accumulation of p27 in S-G(2) phase with overreplication. We demonstrate that Skp2(-/-)p27(-/-) mice do not exhibit the overreplication phenotype, suggesting that p27 accumulation is required for its development. Hepatocytes of Skp2(-/-) mice entered the endoduplication cycle after mitogenic stimulation, whereas this phenotype was not apparent in Skp2(-/-)p27(-/-) mice. Cdc2-associated kinase activity was lower in Skp2(-/-) cells than in wild-type cells, and a reduction in Cdc2 activity was sufficient to induce overreplication. The lack of p27 degradation in G(2) phase in Skp2(-/-) cells may thus result in suppression of Cdc2 activity and consequent inhibition of entry into M phase. These data suggest that p27 proteolysis is necessary for the activation of not only Cdk2 but also Cdc2, and that Skp2 contributes to regulation of G(2)-M progression by mediating the degradation of p27.
Nakayama
Keiko
K
National Institute of Advanced Industrial Science and Technology (AIST), Biological Information Research Center, Tokyo 135-0064, Japan. nakayak1@bioreg.kyushu-u.ac.jp
Nagahama
Hiroyasu
H
Minamishima
Yohji A
YA
Miyake
Satoshi
S
Ishida
Noriko
N
Hatakeyama
Shigetsugu
S
Kitagawa
Masatoshi
M
Iemura
Shun-ichiro
S
Natsume
Tohru
T
Nakayama
Keiichi I
KI
D000818:Animals; D016203:CDC2 Protein Kinase / Q000235:genetics; D042846:CDC2-CDC28 Kinases / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism*; D002467:Cell Nucleus / Q000235:genetics; D051357:Cyclin-Dependent Kinase 2; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004261:DNA Replication / Q000235:genetics; D016195:G2 Phase / Q000235:genetics; D022781:Hepatocytes / Q000378:metabolism; D006965:Hyperplasia / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis / Q000235:genetics*; D010447:Peptide Hydrolases / Q000235:genetics; D010641:Phenotype; D014176:Protein Biosynthesis / Q000235:genetics; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics* / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism*
C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D044786:S-Phase Kinase-Associated Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016203:CDC2 Protein Kinase; D042846:CDC2-CDC28 Kinases; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D010447:Peptide Hydrolases