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

Yoichi Imai, Mineo Kurokawa, Yuko Yamaguchi, Koji Izutsu, Eriko Nitta, Kinuko Mitani, Masanobu Satake, Tetsuo Noda, Yoshiaki Ito, Hisamaru Hirai

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Abstract

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. PEBP2β/CBFβ, 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.

Original languageEnglish
Pages (from-to)1033-1043
Number of pages11
JournalMolecular and cellular biology
Volume24
Issue number3
DOIs
Publication statusPublished - 2004 Feb 1

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Imai, Y., Kurokawa, M., Yamaguchi, Y., Izutsu, K., Nitta, E., Mitani, K., Satake, M., Noda, T., Ito, Y., & Hirai, H. (2004). The Corepressor mSin3A Regulates Phosphorylation-Induced Activation, Intranuclear Location, and Stability of AML1. Molecular and cellular biology, 24(3), 1033-1043. https://doi.org/10.1128/MCB.24.3.1033-1043.2004