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J. Biol. Chem., Vol. 276, Issue 5, 3674-3682, February 2, 2001

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Increased Affinity of c-Myb for CREB-binding Protein (CBP) after CBP-induced Acetylation^*

Yuji Sano^§ and Shunsuke Ishii^¶

From the  Laborartory of Molecular Genetics, RIKEN Tsukuba Institute and the ^¶ CREST (Core Research for Evolutional Science and Technology) Research Project of JST (Japan Science and Technology Corporation), 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan

The c-myb proto-oncogene product (c-Myb) is a sequence-specific DNA-binding protein that functions as a transcriptional activator. The transcriptional coactivator CREB-binding protein (CBP) binds via its KIX domain to the activation domain of c-Myb and mediates c-Myb-dependent transcriptional activation. CBP possesses intrinsic histone acetyltransferase activity, and can acetylate not only histones but also certain transcriptional factors such as GATA1 and p53. Here we demonstrate that the C/H2 domain of CBP, which is critical for the acetyltransferase activity, also directly interacts with the negative regulatory domain (NRD) of c-Myb. Consistent with this observation, CBP acetylated c-Myb in vitro at Lys⁴³⁸ and Lys⁴⁴¹ within the NRD. In addition, CBP acetylated c-Myb in vivo not only at the sites found in this study but also at the p300-induced acetylation sites reported recently. Replacement of lysine by arginine at all of these sites dramatically decreased the trans-activating capacity of c-Myb. The results of transcriptional activation assays with c-Myb acetylation site mutants suggested that acetylation of c-Myb at each of these five sites synergistically enhances c-Myb activity. Mutations of these acetylation sites reduced the strength of the interaction between c-Myb and CBP. Thus, acetylation of c-Myb by CBP increases the trans-activating capacity of c-Myb by enhancing its association with CBP. These results demonstrate a novel molecular mechanism of regulation of c-Myb activity.

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