title: C/EBPβ mediates growth hormone-regulated expression of multiple target genes.
abstract: Regulation of c-Fos transcription by GH is mediated by CCAAT/enhancer binding protein β (C/EBPβ). This study examines the role of C/EBPβ in mediating GH activation of other early response genes, including Cyr61, Btg2, Socs3, Zfp36, and Socs1. C/EBPβ depletion using short hairpin RNA impaired responsiveness of these genes to GH, as seen for c-Fos. Rescue with wild-type C/EBPβ led to GH-dependent recruitment of the coactivator p300 to the c-Fos promoter. In contrast, rescue with C/EBPβ mutated at the ERK phosphorylation site at T188 failed to induce GH-dependent recruitment of p300, indicating that ERK-mediated phosphorylation of C/EBPβ at T188 is required for GH-induced recruitment of p300 to c-Fos. GH also induced the occupancy of phosphorylated C/EBPβ and p300 on Cyr61, Btg2, and Socs3 at predicted C/EBP-cAMP response element-binding protein motifs in their promoters. Consistent with a role for ERKs in GH-induced expression of these genes, treatment with U0126 to block ERK phosphorylation inhibited their GH-induced expression. In contrast, GH-dependent expression of Zfp36 and Socs1 was not inhibited by U0126. Thus, induction of multiple early response genes by GH in 3T3-F442A cells is mediated by C/EBPβ. A subset of these genes is regulated similarly to c-Fos, through a mechanism involving GH-stimulated ERK 1/2 activation, phosphorylation of C/EBPβ, and recruitment of p300. Overall, these studies suggest that C/EBPβ, like the signal transducer and activator of transcription proteins, regulates multiple genes in response to GH.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan 48109-5622, USA.
authors.forename: Tracy X
authors.initials: TX
authors.lastname: Cui
authors.forename: Grace
authors.initials: G
authors.lastname: Lin
authors.forename: Christopher R
authors.initials: CR
authors.lastname: LaPensee
authors.forename: Anda-Alexandra
authors.initials: AA
authors.lastname: Calinescu
authors.forename: Maanjot
authors.initials: M
authors.lastname: Rathore
authors.forename: Cale
authors.initials: C
authors.lastname: Streeter
authors.forename: Graciela
authors.initials: G
authors.lastname: Piwien-Pilipuk
authors.forename: Nathan
authors.initials: N
authors.lastname: Lanning
authors.forename: Hui
authors.initials: H
authors.lastname: Jin
authors.forename: Christin
authors.initials: C
authors.lastname: Carter-Su
authors.forename: Zhaohui S
authors.initials: ZS
authors.lastname: Qin
authors.forename: Jessica
authors.initials: J
authors.lastname: Schwartz
mesh_terms: D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D006224:Cricetinae; D003412:Cricetulus; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D016762:Genes, fos / Q000235:genetics; D013006:Growth Hormone / Q000378:metabolism*; D015151:Immunoblotting; D051379:Mice; D009154:Mutation; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering; D020218:Response Elements; D015398:Signal Transduction / Q000235:genetics; D015533:Transcriptional Activation; D050880:p300-CBP Transcription Factors / Q000378:metabolism
chemical_list: D002070:Butadienes; D022782:CCAAT-Enhancer-Binding Protein-beta; C545013:Cebpb protein, mouse; D009570:Nitriles; D034741:RNA, Small Interfering; C113580:U 0126; D013006:Growth Hormone; D050880:p300-CBP Transcription Factors; D048049:Extracellular Signal-Regulated MAP Kinases