Tang Q Q, Lane M D
Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21209, USA.
Proc Natl Acad Sci U S A. 2000 Nov 7;97(23):12446-50. doi: 10.1073/pnas.220425597.
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.
激素诱导生长停滞的前脂肪细胞会引发有丝分裂克隆扩增，随后CCAAT/增强子结合蛋白（C/EBP）α表达并分化为脂肪细胞。这些事件的顺序至关重要，因为C/EBPα具有抗有丝分裂作用，其过早表达会阻断分化所需的有丝分裂克隆扩增。C/EBPβ是C/EBPα基因的转录激活因子，在分化程序早期表达，但缺乏DNA结合活性，直到前脂肪细胞通过有丝分裂克隆扩增的G(1)-S期检查点才定位于着丝粒。有证据表明，生长停滞的前脂肪细胞表达的显性负性CHOP-10通过异二聚化短暂隔离C/EBPβ。当前脂肪细胞进入S期时，CHOP-10下调，显然将C/EBPβ从抑制性限制中释放出来，并允许C/EBPα基因的反式激活。为支持这些发现，用蛋白酶抑制剂N-乙酰-Leu-Leu-正亮氨酸上调CHOP-10可阻止C/EBPβ的激活、C/EBPα的表达和成脂作用。
