title: The corepressor mSin3A regulates phosphorylation-induced activation, intranuclear location, and stability of AML1.
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. PEBP2 beta/CBF beta, 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.
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Imai
authors.forename: Mineo
authors.initials: M
authors.lastname: Kurokawa
authors.forename: Yuko
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Koji
authors.initials: K
authors.lastname: Izutsu
authors.forename: Eriko
authors.initials: E
authors.lastname: Nitta
authors.forename: Kinuko
authors.initials: K
authors.lastname: Mitani
authors.forename: Masanobu
authors.initials: M
authors.lastname: Satake
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Noda
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Ito
authors.forename: Hisamaru
authors.initials: H
authors.lastname: Hirai
mesh_terms: D000818:Animals; D019556:COS Cells; D002467:Cell Nucleus / Q000378:metabolism; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins / Q000378:metabolism*; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D056572:Histone Deacetylase Inhibitors; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C099683:SIN3A transcription factor; D014157:Transcription Factors; D004815:Epidermal Growth Factor; D020928:Mitogen-Activated Protein Kinases; D006655:Histone Deacetylases; D056264:Sin3 Histone Deacetylase and Corepressor Complex