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| Subject Categories: Cell Cycle | Molecular Biology of Disease |
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| The EMBO Journal
(2005) 24, 1739–1749, doi:10.1038/sj.emboj.7600656 Published online 21 April 2005 |
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| Myeloid leukemia factor 1 regulates p53 by suppressing COP1 via COP9 signalosome subunit 3 |
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| Noriko Yoneda-Kato, Kiichiro Tomoda, Mari Umehara, Yukinobu Arata and Jun-ya Kato |
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Department of Animal Molecular Genetics, Graduate School of Biological Sciences, Nara Institute of Science and Technology, Takayama, Ikoma, Nara, Japan To whom correspondence should be addressed Noriko Yoneda-Kato, Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0101, Japan. Tel.: +81 743 72 5514; Fax: +81 743 72 5519; E-mail: noriko-k@bs.naist.jp Received 24 November 2004; Accepted 31 March 2005; Published online 21 April 2005. |
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| Abstract |
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| Myeloid leukemia factor 1 (MLF1) was first identified as the leukemic fusion protein NPM-MLF1 generated by the t(3;5)(q25.1;q34) chromosomal translocation. Although MLF1 expresses normally in a variety of tissues including hematopoietic stem cells and the overexpression of MLF1 correlates with malignant transformation in human cancer, little is known about how MLF1 is involved in the regulation of cell growth. Here we show that MLF1 is a negative regulator of cell cycle progression functioning upstream of the tumor suppressor p53. MLF1 induces p53-dependent cell cycle arrest in murine embryonic fibroblasts. This action requires a novel binding partner, subunit 3 of the COP9 signalosome (CSN3). A reduction in the level of CSN3 protein with small interfering RNA abrogated MLF1-induced G1 arrest and impaired the activation of p53 by genotoxic stress. Furthermore, ectopic MLF1 expression and CSN3 knockdown inversely affect the endogenous level of COP1, a ubiquitin ligase for p53. Exogenous expression of COP1 overcomes MLF1-induced growth arrest. These results indicate that MLF1 is a critical regulator of p53 and suggest its involvement in leukemogenesis through a novel CSN3–COP1 pathway. |
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| Keywords: COP1, CSN3, MLF1, oncogenesis, p53 |
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Top of page MORE ARTICLES LIKE THISThese links to content published by NPG are automatically generated RESEARCHCircumventing tolerance to a human MDM2-derived tumor antigen by TCR gene transfer Nature Immunology Article (01 Oct 2001) Molecular Systems Biology Article (08 May 2007) Nature Immunology Article (01 Nov 2007) CSN controls NF-κB by deubiquitinylation of IκBα The EMBO Journal Article (21 Mar 2007) |
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