Journal of Biological Chemistry
Volume 276, Issue 52, 28 December 2001, Pages 48937-48943
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PROTEIN SYNTHESIS POST-TRANSLATION MODIFICATION AND DEGRADATION
Degradation of p27Kip1 at the G0-G1 Transition Mediated by a Skp2-independent Ubiquitination Pathway*

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Targeting of the cyclin-dependent kinase inhibitor p27Kip1 for proteolysis has been thought to be mediated by Skp2, the F-box protein component of an SCF ubiquitin ligase complex. Degradation of p27Kip1 at the G0-G1transition of the cell cycle has now been shown to proceed normally inSkp2−/− lymphocytes, whereas p27Kip1 proteolysis during S-G2phases is impaired in these Skp2-deficient cells. Degradation of p27Kip1 at the G0-G1transition was blocked by lactacystin, a specific proteasome inhibitor, suggesting that it is mediated by the ubiquitin-proteasome pathway. The first cell cycle of stimulated Skp2−/−lymphocytes appeared normal, but the second cycle was markedly inhibited, presumably as a result of p27Kip1accumulation during S-G2 phases of the first cell cycle. Polyubiquitination of p27Kip1 in the nucleus is dependent on Skp2 and phosphorylation of p27Kip1 on threonine 187. However, polyubiquitination activity was also detected in the cytoplasm ofSkp2−/− cells, even with a threonine 187 → alanine mutant of p27Kip1 as substrate. These results suggest that a polyubiquitination activity in the cytoplasm contributes to the early phase of p27Kip1degradation in a Skp2-independent manner, thereby promoting cell cycle progression from G0 to G1.

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Published, JBC Papers in Press, October 26, 2001, DOI 10.1074/jbc.M107274200

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This work was supported in part by a grant from the Ministry of Education, Science, Sports, and Culture of Japan; by Nissan Science Foundation; and by a research grant from the Human Frontier Science Program.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.