TY - JOUR
T1 - Skp2-Mediated degradation of p27 regulates progression into mitosis
AU - Nakayama, Keiko
AU - Nagahama, Hiroyasu
AU - Minamishima, Yohji A.
AU - Miyake, Satoshi
AU - Ishida, Noriko
AU - Hatakeyama, Shigetsugu
AU - Kitagawa, Masatoshi
AU - Iemura, Shun ichiro
AU - Natsume, Tohru
AU - Nakayama, Keiichi I.
N1 - Funding Information:
We thank M. Fujita for helpful discussions, R. Tsunematsu, M. Matsumoto, T. Hara, Y. Yamada, K. Shimoharada, S. Matsushita, N. Nishimura, R. Yasukochi, A. Ito, Y. Ono, and other laboratory members for technical assistance, and M. Kimura and C. Sugita for help in preparation of the manuscript. This work was supported in part by a research grant from the Human Frontier Science Program.
PY - 2004/5
Y1 - 2004/5
N2 - Although Skp2 has been thought to mediate the degradation of p27 at the G1-S transition, Skp2 -/- cells exhibit accumulation of p27 in S-G2 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 G2 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 G2-M progression by mediating the degradation of p27.
AB - Although Skp2 has been thought to mediate the degradation of p27 at the G1-S transition, Skp2 -/- cells exhibit accumulation of p27 in S-G2 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 G2 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 G2-M progression by mediating the degradation of p27.
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U2 - 10.1016/S1534-5807(04)00131-5
DO - 10.1016/S1534-5807(04)00131-5
M3 - Article
C2 - 15130491
AN - SCOPUS:2342650733
SN - 1534-5807
VL - 6
SP - 661
EP - 672
JO - Developmental Cell
JF - Developmental Cell
IS - 5
ER -