Degradation of p27Kip1 at the G0-G1 Transition Mediated by a Skp2-independent Ubiquitination Pathway

Taichi Hara, Takumi Kamura, Keiko Nakayama, Kiyotaka Oshikawa, Shigetsugu Hatakeyama, Kei Ichi Nakayama

Research output: Contribution to journalArticle

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Abstract

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-G1 transition of the cell cycle has now been shown to proceed normally in Skp2-/- lymphocytes, whereas p27 Kip1 proteolysis during S-G2 phases is impaired in these Skp2-deficient cells. Degradation of p27Kip1 at the G 0-G1 transition 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 p27Kip1 accumulation during S-G2 phases of the first cell cycle. Polyubiquitination of p27 Kip1 in the nucleus is dependent on Skp2 and phosphorylation of p27Kip1 on threonine 187. However, polyubiquitination activity was also detected in the cytoplasm of Skp2-/- 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 p27Kip1 degradation in a Skp2-independent manner, thereby promoting cell cycle progression from G0 to G 1.

Original languageEnglish
Pages (from-to)48937-48943
Number of pages7
JournalJournal of Biological Chemistry
Volume276
Issue number52
DOIs
Publication statusPublished - 2001 Dec 28
Externally publishedYes

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Ubiquitination
Cell Cycle
Cells
Proteolysis
Degradation
Lymphocytes
G2 Phase
Threonine
S Phase
Cytoplasm
SKP Cullin F-Box Protein Ligases
F-Box Proteins
Phosphorylation
Proteasome Inhibitors
Cyclin-Dependent Kinases
Proteasome Endopeptidase Complex
Ubiquitin
Alanine
Substrates

ASJC Scopus subject areas

  • Biochemistry

Cite this

Degradation of p27Kip1 at the G0-G1 Transition Mediated by a Skp2-independent Ubiquitination Pathway. / Hara, Taichi; Kamura, Takumi; Nakayama, Keiko; Oshikawa, Kiyotaka; Hatakeyama, Shigetsugu; Nakayama, Kei Ichi.

In: Journal of Biological Chemistry, Vol. 276, No. 52, 28.12.2001, p. 48937-48943.

Research output: Contribution to journalArticle

Hara, Taichi ; Kamura, Takumi ; Nakayama, Keiko ; Oshikawa, Kiyotaka ; Hatakeyama, Shigetsugu ; Nakayama, Kei Ichi. / Degradation of p27Kip1 at the G0-G1 Transition Mediated by a Skp2-independent Ubiquitination Pathway. In: Journal of Biological Chemistry. 2001 ; Vol. 276, No. 52. pp. 48937-48943.
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