Article
- The EMBO Journal (2005) 24, 160 - 169
- doi:10.1038/sj.emboj.7600486
Published online: 2 December 2004
Subject Categories:
Enhanced Mdm2 activity inhibits pRB function via ubiquitin-dependent degradation
Chiharu Uchida1, Seiichi Miwa1,2, Kyoko Kitagawa1, Takayuki Hattori1, Tomoyasu Isobe1, Sunao Otani1, Toshiaki Oda1, Haruhiko Sugimura3, Takehiko Kamijo4, Keizou Ookawa5, Hideyo Yasuda6 and Masatoshi Kitagawa1
- Department of Biochemistry 1, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
- Second Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
- First Department of Pathology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
- Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Nagano, Japan
- Second Department of Biochemistry, Hirosaki University School of Medicine, Hirosaki, Aomori, Japan
- Division of Bioscience, Central Laboratory, Nippon Flour Mills Co., Ltd., Atsugi, Kanagawa, Japan
Correspondence to:
Masatoshi Kitagawa, Department of Biochemistry 1, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka 431-3192, Japan. Tel.: +81 53 435 2322; Fax: +81 53 435 2322; E-mail: kitamasa@hama-med.ac.jp
Received 4 June 2004; Accepted 27 October 2004
Abstract
Retinoblastoma gene product (pRB) plays critical roles in regulation of the cell cycle and tumor suppression. It is known that downregulation of pRB can stimulate carcinogenesis via abrogation of the pRB pathway, although the mechanism has not been elucidated. In this study, we found that Mdm2, a ubiquitin ligase for p53, promoted ubiquitin-dependent degradation of pRB. pRB was efficiently ubiquitinated by wild-type Mdm2 in vivo as well as in vitro, but other RB family proteins were not. Mutant Mdm2 with a substitution in the RING finger domain showed dominant-negative stabilization of pRB. Both knockout and knockdown of Mdm2 caused accumulation of pRB. Moreover, Mdm2 inhibited pRB-mediated flat formation of Saos-2 cells. Downregulation of pRB expression was correlated with a high level of expression of Mdm2 in human lung cancers. These results suggest that Mdm2 regulates function of pRB via ubiquitin-dependent degradation of pRB.
Keywords:
- Mdm2,
- p53,
- RB protein,
- tumor suppressor,
- ubiquitin ligase
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated
REVIEWS
Amyloid-β immunotherapy for Alzheimer's disease: the end of the beginning
Nature Reviews Neuroscience Perspective (01 Oct 2002)
Pathogenesis of parkinson's disease: dopamine, vesicles and α-synuclein
Nature Reviews Neuroscience Review (01 Dec 2002)
RESEARCH
Oncogene Original Article
Nature Cell Biology Letter (01 Feb 2007)
