CCAAT/enhancer binding protein alpha regulates p21 protein and hepatocyte proliferation in newborn mice
CCAAT/enhancer binding protein alpha regulates p21 protein and hepatocyte proliferation in newborn mice
复制标题
DOI：
10.1128/mcb.17.12.7353
复制
发表时间：
1997-12-01
影响因子：
5.3
通讯作者：
Darlington, GJ
中科院分区：
文献类型：
--
作者：
Timchenko, NA;Harris, TE;Darlington, GJ
CCAAT/增强子结合蛋白α（C/EBP α）在静止的肝细胞和分化的脂肪细胞中以高水平表达。在培养的细胞中，C/EBP α通过稳定p21蛋白部分抑制细胞增殖。本文介绍了C/EBP α在体内调节肝细胞增殖中的作用。在C/EBP α基因敲除的新生小鼠中，肝脏中的p21蛋白水平降低，肝细胞合成DNA的比例增加。当野生型同窝仔中的细胞分裂较低（3%）时，C/EBP α敲除动物中超过30%的肝细胞在出生后第17天继续增殖。p21蛋白水平在野生型新生儿中相对较高，但在C/EBP α敲除小鼠中检测不到。缺乏C/EBP α的高度增殖肝脏中p21蛋白的减少表明p21负责新生小鼠中C/EBP α介导的肝脏增殖控制。在大鼠肝再生过程中，C/EBP α和p21蛋白的量在DNA合成前（6至12小时）降低，然后在48小时恢复到手术前水平。虽然C/EBP α控制p21蛋白水平，但p21 mRNA在肝脏中不受C/EBP α的影响。使用免疫共沉淀和哺乳动物双杂交检测系统，我们已经显示了C/EBP α和p21蛋白的相互作用。肝核提取物中p21稳定性的研究表明，C/EBP α阻断p21的蛋白水解降解。我们的数据表明，C/EBP α调节新生小鼠的肝细胞增殖，在肝脏中，p21蛋白的水平是在转录后控制，与蛋白质-蛋白质相互作用与C/EBP α决定p21水平的假设一致。
CCAAT/enhancer binding protein alpha (C/EBP alpha) is expressed at high levels in quiescent hepatocytes and in differentiated adipocytes. In cultured cells, C/EBP alpha inhibits cell proliferation in part via stabilization of the p21 protein. The role of C/EBP alpha in regulating hepatocyte proliferation in vivo is presented herein. In C/EBP alpha knockout newborn mice, p21 protein levels are reduced in the liver, and the fraction of hepatocytes synthesizing DNA is increased. Greater than 30% of the hepatocytes in C/EBP alpha knockout animals continue to proliferate at day 17 of postnatal life when cell division in wild-type littermates is low (3%). p21 protein levels are relatively high in wild type neonates but undetectable in C/EBP alpha knockout mice. The reduction of p21 protein in the highly proliferating livers that lack C/EBP alpha suggests that p21 is responsible for C/EBP alpha-mediated control of liver proliferation in newborn mice. During rat liver regeneration, the amounts of both C/EBP alpha and p21 proteins are decreased before DNA synthesis (6 to 12 h) and then return to presurgery levels at 48 h. Although C/EBP alpha controls p21 protein levels, p21 mRNA is not influenced by C/EBP alpha in liver. Using coimmunoprecipitation and a mammalian two hybrid assay system, we have shown the interaction of C/EBP alpha and p21 proteins. Study of p21 stability in liver nuclear extracts showed that C/EBP alpha blocks proteolytic degradation of p21. Our data demonstrate that C/EBP alpha regulates hepatocyte proliferation in newborn mice and that in liver, the level of p21 protein is under posttranscriptional control, consistent with the hypothesis that protein-protein interaction with C/EBP alpha determines p21 levels.