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J. Biol. Chem., Vol. 281, Issue 20, 14494-14502, May 19, 2006

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N-terminal Region of CCAAT/Enhancer-binding Protein Is Critical for Cell Cycle Arrest, Apoptosis, and Functional Maturation during Myeloid Differentiation^*

Hideaki Nakajima¹², Naohide Watanabe¹, Fumi Shibata^¶, Toshio Kitamura^¶, Yasuo Ikeda^||, and Makoto Handa

From the Center of Excellence, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan, the Department of Transfusion and Cell Therapy and the ^||Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan, and the ^¶Division of Cellular Therapy, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan

CCAAT/enhancer-binding protein (C/EBP) plays a critical role in terminal myeloid differentiation. Differentiation is an integrated process of cell cycle arrest, morphological change, functional maturation, and apoptosis. However, the molecular networks underlying these events in C/EBP-induced differentiation remain poorly understood. To reveal these mechanisms, we performed a detailed molecular analysis of C/EBP-induced differentiation using an inducible form of C/EBP. The activation of C/EBP induced growth arrest, morphological differentiation, the expression of CD11b and secondary granule proteins, and apoptosis in myeloid cell lines. Unlike C/EBP, C/EBP dramatically up-regulated p27 with a concomitant down-regulation of cdk4/6 and cyclin D2/A/E. Moreover, the anti-apoptotic proteins Bcl-2 and Bcl-x were down-regulated, whereas pro-apoptotic protein Bax remained unchanged. Using a variety of mutants, we revealed that these events were all regulated by the N-terminal activation domain of C/EBP. Interestingly, some of the differentiation processes such as the induction of secondary granule protein genes were clearly inhibited by c-Myc; however, inhibition of apoptosis by Bcl-x did not affect the entire differentiation processes. These data indicate the N terminus of C/EBP to be solely responsible for most aspects of myeloid differentiation, and these events were differentially affected by c-Myc.

Received for publication, January 19, 2006 , and in revised form, March 10, 2006.

^* This work was supported in part by grants from the Ministry of Education, Science, Sports and Culture of Japan and the Naito Foundation. 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 Fig. S1.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: Center of Excellence, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokane-dai, Minato-ku, Tokyo 108-8639, Japan. Tel.: 81-3-5449-5759; Fax: 81-3-5449-5453; E-mail: hnakajim{at}ims.u-tokyo.ac.jp.

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