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J. Biol. Chem., Vol. 283, Issue 9, 5939-5949, February 29, 2008

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Hes6 Controls Cell Proliferation via Interaction with cAMP-response Element-binding Protein-binding Protein in the Promyelocytic Leukemia Nuclear Body^*

Bokkee Eun, Yool Lee, Soontaek Hong, Jaesang Kim^¶, Han-Woong Lee^||, Kyungjin Kim, Woong Sun¹, and Hyun Kim²

From the College of Medicine, Brain Korea 21, Korea University, Seoul 136-705, School of Biological Sciences, Seoul National University, Seoul 151-742, ^¶Division of Molecular Life Sciences, Ewha Womans University, Seoul 120-750, and ^||College of Science, Yonsei University, Seoul 120-749, Korea

Hes6 is a basic helix-loop-helix transcription factor that functions in the differentiation of pluripotent progenitor cells and during tumorigenesis. However, the molecular mechanism for its function is largely unknown. Here we show that Hes6 is a component of the promyelocytic leukemia nuclear body (PML-NB) complex in the nuclei and that Hes6 inhibits cell proliferation through induction of p21 cyclin-dependent kinase inhibitor. We further show that Hes6 directly interacts with CREB-binding protein (CBP), one of the key components of PML-NB, via its basic domain. This association is critical for p21 induction through multiple mechanisms, including chromatin remodeling and p53 acetylation. Taken together, these results suggest that the Hes6-CBP complex in PML-NB may influence the proliferation of cells via p53-dependent and -independent pathways.

Received for publication, September 13, 2007 , and in revised form, December 21, 2007.

^* This work was supported by Korea Science and Engineering Foundation Grant M1050000004905J000004900 (to H. K.), Korea Research Foundation Grant KRF-2006-312-C00645 (to W. S.), and in part by the Core Facility Service of the 21st Century Frontier Brain Research Center Grant M103KV010018-03K2201-01820 (to H. K.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S4.

¹ To whom correspondence may be addressed: Dept. of Anatomy, Korea University College of Medicine, 126-1 Anam-Dong, Sungbuk-Gu, Seoul, Korea. Tel.: 82-2-920-6153-6404; Fax: 82-2-929-5696; E-mail: woongsun{at}korea.ac.kr.

² To whom correspondence may be addressed. Tel.: 82-2-920-6153-6404; Fax: 82-2-929-5696; E-mail: kimhyun{at}korea.ac.kr.

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