| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Molecular Biology, Pathobiology, and Genetics |
1 Department of Biochemistry 1 and 2 Second Department of Surgery, Hamamatsu University School of Medicine, Higashi-ku, Hamamatsu, Japan
Requests for reprints: Masatoshi Kitagawa, Department of Biochemistry 1, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan. Phone: 81-53-435-2322; Fax: 81-53-435-2322; E-mail: kitamasa{at}hama-med.ac.jp.
The cyclin-dependent kinase inhibitor p27Kip1 is degraded in late G1 phase by the ubiquitin-proteasome pathway, allowing cells to enter S phase. Due to accelerated degradation of p27Kip1, various human cancers express low levels of p27Kip1 associated with poor prognosis. S-phase kinase–associated protein 2, the F-box protein component of an SCF ubiquitin ligase complex, is implicated in degradation of p27Kip1 during S-G2 phases. Recently, Kip1 ubiquitination–promoting complex has been reported as another ubiquitin ligase that targets cytoplasmic p27Kip1 exported from the nucleus in G0-G1 phases. Here, we identified a RING-H2–type ubiquitin ligase, Pirh2, as a p27Kip1-interacting protein. Endogenous Pirh2 physically interacted with endogenous p27Kip1 in mammalian cells. Pirh2 directly ubiquitinated p27Kip1 in an intact RING finger domain-dependent manner in vivo, as well as in vitro. Ablation of endogenous Pirh2 by small interfering RNA increased the steady-state level of p27Kip1 and decelerated p27Kip1 turnover. Depletion of Pirh2 induced accumulation of p27Kip1 in both the nucleus and cytoplasm. Pirh2 expression was induced from late G1-S phase, whereas p27Kip1 was decreased in synchronization with accumulation of Pirh2. Furthermore, reduction of Pirh2 resulted in an impairment of p27Kip1 degradation and an inhibition of cell cycle progression at G1-S transition in a p53-independent manner. Overall, the results indicate that Pirh2 acts as a negative regulator of p27Kip1 function by promoting ubiquitin-dependent proteasomal degradation. [Cancer Res 2007;67(22):10789–95]
This article has been cited by other articles:
![]() |
E. Susaki, K. Nakayama, L. Yamasaki, and K. I. Nakayama Common and specific roles of the related CDK inhibitors p27 and p57 revealed by a knock-in mouse model PNAS, March 31, 2009; 106(13): 5192 - 5197. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. M. Bertagnolli, R. S. Warren, D. Niedzwiecki, E. Mueller, C. C. Compton, M. Redston, M. Hall, H. P. Hahn, S. D. Jewell, R. J. Mayer, et al. p27Kip1 in Stage III Colon Cancer: Implications for Outcome following Adjuvant Chemotherapy in Cancer and Leukemia Group B Protocol 89803 Clin. Cancer Res., March 15, 2009; 15(6): 2116 - 2122. [Abstract] [Full Text] [PDF] |
||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |