AML1 is functionally regulated through p300-mediated acetylation on specific lysine residues

Yuko Yamaguchi; Mineo Kurokawa; Yoichi Imai; Koji Izutsu; Takashi Asai; Motoshi Ichikawa; Go Yamamoto; Eriko Nitta; Tetsuya Yamagata; Kazuki Sasaki; Kinuko Mitani; Seishi Ogawa; Shigeru Chiba; Hisamaru Hirai

doi:10.1074/jbc.M400355200

AML1 is functionally regulated through p300-mediated acetylation on specific lysine residues

J Biol Chem. 2004 Apr 9;279(15):15630-8. doi: 10.1074/jbc.M400355200. Epub 2004 Jan 29.

Authors

Yuko Yamaguchi¹, Mineo Kurokawa, Yoichi Imai, Koji Izutsu, Takashi Asai, Motoshi Ichikawa, Go Yamamoto, Eriko Nitta, Tetsuya Yamagata, Kazuki Sasaki, Kinuko Mitani, Seishi Ogawa, Shigeru Chiba, Hisamaru Hirai

Affiliation

¹ Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, USA.

PMID: 14752096
DOI: 10.1074/jbc.M400355200

Abstract

AML1 (RUNX1) is one of the most frequently disrupted genes in human leukemias. AML1 encodes transcription factors, which play a pivotal role in hematopoietic differentiation, and their inappropriate expression is associated with leukemic transformation of hematopoietic cells. Previous studies demonstrated that the transcription cofactor p300 binds to the C-terminal region of AML1 and stimulates AML1-dependent transcription during myeloid cell differentiation. Here, we report that AML1 is specifically acetylated by p300 in vitro. Mutagenesis analyses reveal that p300 acetylates AML1 at the two conserved lysine residues (Lys-24 and Lys-43). AML1 is subject to acetylation at the same sites in vivo, and p300-mediated acetylation significantly augments the DNA binding activity of AML1. Disruption of these two lysines severely impairs DNA binding of AML1 and reduced the transcriptional activity and the transforming potential of AML1. Taken together, these data indicate that acetylation of AML1 through p300 is a critical manner of posttranslational modification and identify a novel mechanism for regulating the function of AML1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylation
Animals
COS Cells
Cell Differentiation
Cell Line
Cell Line, Tumor
Core Binding Factor Alpha 2 Subunit
DNA / chemistry
DNA Mutational Analysis
DNA-Binding Proteins / biosynthesis*
DNA-Binding Proteins / genetics*
E1A-Associated p300 Protein
Gene Expression Regulation*
Glutathione Transferase / metabolism
HeLa Cells
Hematopoietic Stem Cells / cytology
Humans
Immunoblotting
Luciferases / metabolism
Lysine / chemistry*
Mice
Models, Biological
Mutation
NIH 3T3 Cells
Nuclear Proteins / metabolism*
Plasmids / metabolism
Precipitin Tests
Protein Binding
Protein Structure, Tertiary
Proto-Oncogene Proteins / biosynthesis*
Proto-Oncogene Proteins / genetics*
Recombinant Fusion Proteins / metabolism
Recombinant Proteins / metabolism
Trans-Activators / metabolism*
Transcription Factors / biosynthesis*
Transcription Factors / genetics*

Substances

Core Binding Factor Alpha 2 Subunit
DNA-Binding Proteins
Nuclear Proteins
Proto-Oncogene Proteins
RUNX1 protein, human
Recombinant Fusion Proteins
Recombinant Proteins
Runx1 protein, mouse
Trans-Activators
Transcription Factors
DNA
Luciferases
E1A-Associated p300 Protein
Ep300 protein, mouse
Glutathione Transferase
Lysine