Profiles of growth hormone (GH)-regulated genes reveal time-dependent responses and identify a mechanism for regulation of activating transcription factor 3 by GH.
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 (GADD45gamma) showed similar time-dependent patterns of responses to GH, suggesting similar regulatory mechanisms. A conserved sequence in the promoters of the Atf3 and Gadd45gamma genes contains a CCAAT/enhancer-binding protein (C/EBP) site previously observed in the Gadd45gamma promoter, suggesting a novel corresponding C/EBP site in the Atf3 promoter. C/EBPbeta was found to bind to the predicted Atf3 C/EBP site, and C/EBPbeta 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/EBPbeta but also by GH. These findings suggest that GH regulates transcription of Atf3 through a mechanism utilizing factors, such as C/EBPbeta, which bind to a novel C/EBP site.
Huo
Jeffrey S
JS
Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, 48109, USA.
McEachin
Richard C
RC
Cui
Tracy Xiao
TX
Duggal
Nisha K
NK
Hai
Tsonwin
T
States
David J
DJ
Schwartz
Jessica
J
D016475:3T3 Cells; D051700:Activating Transcription Factor 3 / Q000235:genetics*; D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000502:physiology; D002784:Cholesterol / Q000096:biosynthesis; D005227:Fatty Acids / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000187:drug effects*; D013006:Growth Hormone / Q000494:pharmacology*; D051379:Mice; D011401:Promoter Regions, Genetic; D013997:Time Factors; D014158:Transcription, Genetic
D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; D022782:CCAAT-Enhancer-Binding Protein-beta; D005227:Fatty Acids; D013006:Growth Hormone; D002784:Cholesterol