Role of C/EBP homologous protein (CHOP-10) in the programmed activation of CCAAT/enhancer-binding protein-beta during adipogenesis.
Hormone induction of growth-arrested preadipocytes triggers mitotic clonal expansion followed by expression of CCAAT/enhancer-binding protein (C/EBP)alpha and differentiation into adipocytes. The order of these events is critical because C/EBPalpha is antimitotic and its expression prematurely would block the mitotic clonal expansion required for differentiation. C/EBPbeta, a transcriptional activator of the C/EBPalpha gene, is expressed early in the differentiation program, but lacks DNA-binding activity and fails to localize to centromeres until preadipocytes traverse the G(1)-S checkpoint of mitotic clonal expansion. Evidence is presented that dominant-negative CHOP-10 expressed by growth-arrested preadipocytes transiently sequesters C/EBPbeta by heterodimerization. As preadipocytes reach S phase, CHOP-10 is down-regulated, apparently releasing C/EBPbeta from inhibitory constraint and allowing transactivation of the C/EBPalpha gene. In support of these findings, up-regulation of CHOP-10 with the protease inhibitor N-acetyl-Leu-Leu-norleucinal prevents activation of C/EBPbeta, expression of C/EBPalpha, and adipogenesis.
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Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21209, USA. qqtang@welchlink.welch.jhu.edu
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D016475:3T3 Cells; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics* / Q000378:metabolism; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002454:Cell Differentiation; D002503:Centromere / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D015536:Down-Regulation; D051379:Mice; D010641:Phenotype; D015534:Trans-Activators / Q000378:metabolism*; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation
D022763:CCAAT-Enhancer-Binding Protein-alpha; D022782:CCAAT-Enhancer-Binding Protein-beta; D022762:CCAAT-Enhancer-Binding Proteins; C497250:Ddit3 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D051742:Transcription Factor CHOP; D004247:DNA