HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 281, Issue 10, 6734-6741, March 10, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/10/6734    most recent M513014200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ikeda, H. Articles by Sakai, M. Search for Related Content PubMed PubMed Citation Articles by Ikeda, H. Articles by Sakai, M. Social Bookmarking                      What's this?

CCAAT Enhancer-binding Protein Suppresses the Rat Placental Glutathione S-Transferase Gene in Normal Liver^*

Hiromi Ikeda, Kazuki Omoteyama, Kazuhiko Yoshida, Shinzo Nishi, and Masaharu Sakai^¶1

From the Departments of Biochemistry and Ophthalmology, Hokkaido University Graduate School of Medicine, N15, W7, Kita-Ku, Sapporo 060-8638, Japan and the ^¶Department of Health Sciences, Hokkaido University School of Medicine, N12, W5, Kita-Ku, Sapporo 060-0812, Japan

The rat placental glutathione S-transferase (GST-P), an isozyme of glutathione S-transferase, is not expressed in normal liver but is highly induced at an early stage of chemical hepatocarcinogenesis and in hepatomas. Recently, we reported that the NF-E2 p45-related factor 2 (Nrf2)/MafK heterodimer binds to GST-P enhancer 1 (GPE1), a strong enhancer of the GST-P gene, and activates this gene in preneoplastic lesions and hepatomas. In addition to the positive regulation during hepatocarcinogenesis, negative regulatory mechanisms might work to repress GST-P in normal liver, but this remains to be clarified. In this work, we identify the CCAAT enhancer-binding protein (C/EBP) as a negative regulator that binds to GPE1 and suppresses GST-P expression in normal liver. C/EBP binds to part of the GPE1 sequence, and the binding of Nrf2/MafK and C/EBP to GPE1 is mutually exclusive. In a transient-transfection analysis, C/EBP activated GPE1 in F9 embryonal carcinoma cells but strongly inhibited GPE1 activity in hepatoma cells. The expression of C/EBP was specifically suppressed in GST-P-positive preneoplastic foci in the livers of carcinogentreated rats. A chromatin immunoprecipitation analysis showed that C/EBP bound to GPE1 in the normal liver in vivo but did not bind in preneoplastic hepatocytes. Introduction of the C/EBP gene fused with the estrogen receptor ligand-binding domain into hepatoma cells, and subsequent activation by -estradiol led to the suppression of endogenous GST-P expression. These results indicate that C/EBP is a negative regulator of GST-P gene expression in normal liver.

Received for publication, December 6, 2005 , and in revised form, January 5, 2006.

^* This work was supported by grants-in-aid from the Saitama Medical School Research Center for Genomic Medicine, Ministry of Education, Science, Sports and Culture of Japan, and the YASUDA Medical Research 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.

¹ To whom correspondence should be addressed: Dept. of Health Sciences, Hokkaido University School of Medicine, N12, W5, Kita-Ku, Sapporo 060-0812, Japan. Tel.: 81-11-706-3407; Fax: 81-11-706-3407; E-mail: m_sakai{at}med.hokudai.ac.jp.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				J. Y. Lee, C. Y. Han, J. W. Yang, C. Smith, S. K. Kim, E. Y.-H. P. Lee, S. G. Kim, and K. W. Kang Induction of Glutathione Transferase in Insulin-Like Growth Factor Type I Receptor-Overexpressed Hepatoma Cells Mol. Pharmacol., October 1, 2007; 72(4): 1082 - 1093. [Abstract] [Full Text] [PDF]

				P. J. McFie, G.-L. Wang, N. A. Timchenko, H. L. Wilson, X. Hu, and W. J. Roesler Identification of a Co-repressor That Inhibits the Transcriptional and Growth-Arrest Activities of CCAAT/Enhancer-binding Protein {alpha} J. Biol. Chem., June 30, 2006; 281(26): 18069 - 18080. [Abstract] [Full Text] [PDF]