Genes: Structure and Regulation
AML1 Is Functionally Regulated through p300-mediated Acetylation on Specific Lysine Residues*

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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.

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This work was partially supported by a fellowship from the Ministry of Education, Culture, Sports, Science and Technology of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

†

Hisamaru Hirai died suddenly on August 23, 2003. His students, fellows, and colleagues will greatly miss his energetic and nurturing leadership in the field of hematology. We dedicate this paper in his memory.

© 2004 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.