TY - JOUR
T1 - The Corepressor mSin3A Regulates Phosphorylation-Induced Activation, Intranuclear Location, and Stability of AML1
AU - Imai, Yoichi
AU - Kurokawa, Mineo
AU - Yamaguchi, Yuko
AU - Izutsu, Koji
AU - Nitta, Eriko
AU - Mitani, Kinuko
AU - Satake, Masanobu
AU - Noda, Tetsuo
AU - Ito, Yoshiaki
AU - Hirai, Hisamaru
PY - 2004/2
Y1 - 2004/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=9144235404&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=9144235404&partnerID=8YFLogxK
U2 - 10.1128/MCB.24.3.1033-1043.2004
DO - 10.1128/MCB.24.3.1033-1043.2004
M3 - Article
C2 - 14729951
AN - SCOPUS:9144235404
VL - 24
SP - 1033
EP - 1043
JO - Molecular and Cellular Biology
JF - Molecular and Cellular Biology
SN - 0270-7306
IS - 3
ER -