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Molecular and Cellular Biology, February 2004, p. 1033-1043, Vol. 24, No. 3
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.3.1033-1043.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

The Corepressor mSin3A Regulates Phosphorylation-Induced Activation, Intranuclear Location, and Stability of AML1

Yoichi Imai,1 Mineo Kurokawa,1* Yuko Yamaguchi,1 Koji Izutsu,1 Eriko Nitta,1 Kinuko Mitani,2 Masanobu Satake,3 Tetsuo Noda,4 Yoshiaki Ito,5 and Hisamaru Hirai1

Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-8655,1 Department of Hematology, Dokkyo University School of Medicine, Tochigi 321-0207,2 Department of Molecular Immunology, Institute of Development, Aging, and Cancer, Tohoku University, Sendai 980-0872,3 Department of Cell Biology, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo 170-0012, Japan,4 Institute of Molecular and Cell Biology, National University of Singapore, Singapore 117609, Singapore5

Received 17 March 2003/ Returned for modification 8 May 2003/ Accepted 31 October 2003

The AML1 (RUNX1) gene, one of the most frequent targets of translocations associated with human leukemias, encodes a DNA-binding protein that plays pivotal roles in myeloid differentiation through transcriptional regulation of various genes. Previously, we reported that AML1 is phosphorylated on two serine residues with dependence on activation of extracellular signal-regulated kinase, which positively regulates the transcriptional activity of AML1. Here, we demonstrate that the interaction between AML1 and the corepressor mSin3A is regulated by phosphorylation of AML1 and that release of AML1 from mSin3A induced by phosphorylation activates its transcriptional activity. Furthermore, phosphorylation of AML1 regulates its intranuclear location and disrupts colocalization of AML1 with mSin3A in the nuclear matrix. PEBP2ß/CBFß, a heterodimeric partner of AML1, was shown to play a role in protecting AML1 from proteasome-mediated degradation. We show that mSin3A also protects AML1 from proteasome-mediated degradation and that phosphorylation-induced release of AML1 from mSin3A results in degradation of AML1 in a time-dependent manner. This study provides a novel regulatory mechanism for the function of transcription factors mediated by protein modification and interaction with cofactors.

* Corresponding author. Mailing address: Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Phone: 81-3-38150-5411, ext. 33118. Fax: 81-3-3815-8350. E-mail: kurokawa-tky{at}umin.ac.jp.

Molecular and Cellular Biology, February 2004, p. 1033-1043, Vol. 24, No. 3
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.3.1033-1043.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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