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J. Biol. Chem., Vol. 281, Issue 31, 21629-21639, August 4, 2006

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Sumoylation of CCAAT/Enhancer-binding Protein and Its Functional Roles in Hepatocyte Differentiation^*

Yoshitaka Sato¹, Katsuhide Miyake², Hidenori Kaneoka, and Shinji Iijima

From the Department of Biotechnology, Graduate School of Engineering and Ecotopia Science Institute, Nagoya University, Nagoya 464-8603, Japan

The sumoylation of CCAAT/enhancer-binding proteins (C/EBPs) by small ubiquitin-related modifier-1 (SUMO-1) has been reported recently. In this study, we investigated the functional role of the sumoylation of C/EBP in the differentiation of hepatocytes. The amount of sumoylated C/EBP gradually decreased during the differentiation, which suggests that the sumoylation is important for the control of growth/differentiation especially in the fetal liver. To analyze the function of the sumoylation of C/EBP in liver-specific gene expression, we studied its effects on the expression of the albumin gene. The C/EBP-mediated transactivation of the albumin gene was reduced by sumoylation of C/EBP in primary fetal hepatocytes. The enhancement of C/EBP-mediated transactivation by BRG1, a core subunit of the SWI/SNF chromatin remodeling complex, was hampered by sumoylation in a luciferase reporter assay. In addition, we discovered that sumoylation of C/EBP blocked its inhibitory effect on cell proliferation by leading to the disruption of a proliferation-inhibitory complex because of a failure of the sumoylated C/EBP to interact with BRG1. BRG1 was recruited to the dihydrofolate reductase promoter in nonproliferating C33a cells but was not detected in proliferating cells where C/EBP, BRG1, and SUMO-1 were overexpressed. This result suggests that BRG1 down-regulates the expression of the dihydrofolate reductase gene. These findings provide the insight that SUMO acts as a space regulator, which affects protein-protein interactions.

Received for publication, January 27, 2006 , and in revised form, May 17, 2006.

^* 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 and S2.

¹ Present address: Dept. of Virology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, and Division of Virology, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan.

² To whom correspondence should be addressed. Tel.: 81-52-789-4278; Fax: 81-52-789-3221; E-mail: miyake{at}proc.nubio.nagoya-u.ac.jp.

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