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Updated: Jan 24, 2026
Live Cell Imaging of Chromosome Segregation During Mitosis
Published on: March 14, 2018
Skp2-mediated degradation of p27 regulates progression into mitosis
Keiko Nakayama1, Hiroyasu Nagahama, Yohji A Minamishima
1National Institute of Advanced Industrial Science and Technology (AIST), Biological Information Research Center, Tokyo 135-0064, Japan. nakayak1@bioreg.kyushu-u.ac.jp
Abstract:
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.
Insights
Skp2 normally degrades p27 to allow cell cycle progression. Without Skp2, p27 accumulates, causing cell overreplication, but only if p27 is present.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Skp2 is known to degrade p27 at the G(1)-S transition.
- Skp2-deficient cells show p27 accumulation in S-G(2) and overreplication.
Purpose of the Study:
- To investigate the role of p27 accumulation in Skp2-deficient cell overreplication.
- To elucidate the function of Skp2 in cell cycle regulation beyond the G(1)-S transition.
Main Methods:
- Generation and analysis of Skp2(-/-) and Skp2(-/-)p27(-/-) mice.
- Cell cycle analysis of hepatocytes following mitogenic stimulation.
- Measurement of Cdc2-associated kinase activity.
Main Results:
- Skp2(-/-)p27(-/-) mice lack the overreplication phenotype seen in Skp2(-/-) mice, indicating p27 accumulation is essential for this phenotype.
- Hepatocytes from Skp2(-/-) mice undergo endoduplication, which is absent in Skp2(-/-)p27(-/-) mice.
- Reduced Cdc2 activity in Skp2(-/-) cells correlates with overreplication, and this reduction is linked to p27 accumulation in G(2) phase.
Conclusions:
- p27 accumulation, not just the absence of Skp2, drives the overreplication phenotype.
- Skp2-mediated p27 degradation is crucial for activating both Cdk2 and Cdc2.
- Skp2 regulates G(2)-M phase progression by controlling p27 degradation, impacting Cdc2 activity and M phase entry.
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