Role of C/EBP homologous protein (CHOP-10) in the programmed activation ofCCAAT/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)a lpha and differentiation into adipocytes. The order of these events is crit ical because C/EBP alpha is antimitotic and its expression prematurely woul d block the mitotic: clonal expansion required for differentiation. C/EBP b eta, a transcriptional activator of the C/EBP alpha gene, is expressed earl y in the differentiation program. but lacks DNA-binding activity and fails to localize to centromeres until preadipocytes traverse the G(1)-S checkpoi nt of mitotic clonal expansion. Evidence is presented that dominant-negativ e CHOP-10 expressed by growth-arrested preadipocytes transiently sequesters C/EBP beta by heterodimerization. As preadipocytes reach S phase, CHOP-10 is down-regulated, apparently releasing C/EBP beta from inhibitory constrai nt and allowing transactivation of the C/EBP alpha gene. In support of thes e findings, up-regulation of CHOP-10 with the protease inhibitor N-acetyl-L eu-Leu-norleucinal prevents activation of C/EBP beta. expression of C/EBP a lpha, and adipogenesis.