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J. Biol. Chem., Vol. 281, Issue 7, 4132-4141, February 17, 2006

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Profiles of Growth Hormone (GH)-regulated Genes Reveal Time-dependent Responses and Identify a Mechanism for Regulation of Activating Transcription Factor 3 By GH^*

Jeffrey S. Huo¹, Richard C. McEachin², Tracy Xiao Cui^¶, Nisha K. Duggal^¶, Tsonwin Hai^||, David J. States, and Jessica Schwartz^¶3

From the Program in Cellular and Molecular Biology, the Department of Human Genetics and Bioinformatics Program, and the ^¶Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, and the ^||Department of Molecular and Cellular Biochemistry, Ohio State University, Columbus, Ohio 43210

In examination of mechanisms regulating metabolic responses to growth hormone (GH), microarray analysis identified 561 probe sets showing time-dependent patterns of expression in GH-treated 3T3-F442A adipocytes. Biological functions significantly over-represented among GH-regulated genes include regulators of transcription at early times, and lipid biosynthesis, cholesterol biosynthesis, and mediators of immune responses at later times (48 h). One novel GH-induced gene encodes activating transcription factor 3 (ATF3). Atf3 mRNA expression and promoter activity were stimulated by GH. Genes for ATF3 and growth arrest and DNA damage-inducible gene 45 gamma (GADD45) showed similar time-dependent patterns of responses to GH, suggesting similar regulatory mechanisms. A conserved sequence in the promoters of the Atf3 and Gadd45 genes contains a CCAAT/enhancer-binding protein (C/EBP) site previously observed in the Gadd45 promoter, suggesting a novel corresponding C/EBP site in the Atf3 promoter. C/EBP was found to bind to the predicted Atf3 C/EBP site, and C/EBP enhanced the activation of the wild-type Atf3 promoter. Mutation of the predicted Atf3 C/EBP site disrupted Atf3 promoter activation not only by C/EBP but also by GH. These findings suggest that GH regulates transcription of Atf3 through a mechanism utilizing factors, such as C/EBP, which bind to a novel C/EBP site.

Received for publication, August 2, 2005 , and in revised form, October 24, 2005.

^* This work was supported in part by National Institutes of Health (NIH) Grants DK46072 (to J. S.), LM008106 (to D. J. S.), and DK59605 (to T. H.), by National Science Foundation (NSF) Grant IBN-0080193 (to J. S.), a Bioinformatics Pilot Research Grant from the Howard Hughes Medical Institute (to J. S.), and a grant from the Biomedical Research Council at the University of Michigan (to J. S.). Microarray analysis was performed through the Michigan Diabetes Research and Training Center (NIH Grant DK58771). 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 Tables S1–S3.

¹ Supported by the Cellular and Molecular Biology Training Grant (NIH Grant T32-GM07315), a National Defense Science and Engineering Graduate (NDSEG) predoctoral fellowship from the U.S. Dept. of Defense, and an NSF Graduate Fellowship.

² Supported by fellowships from the National Human Genome Research Institute and the Hazen Memorial Fund. Current address: Michigan Center for Biological Information, University of Michigan, Ann Arbor, MI 48105.

³ To whom correspondence should be addressed: Dept of Molecular and Integrative Physiology, University of Michigan, 6815 Med. Sci. II, 1301 Catherine St., Ann Arbor, MI 48109-0622. Tel.: 734-647-2124; Fax: 734-647-9523; E-mail: jeschwar{at}umich.edu.

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