Lipid synthetic transcription factor SREBP-1a activates p21WAF1/CIP1, a universal cyclin-dependent kinase inhibitor
Lipid synthetic transcription factor SREBP-1a activates p21WAF1/CIP1, a universal cyclin-dependent kinase inhibitor
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DOI：
10.1128/mcb.25.20.8938-8947.2005
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发表时间：
2005-10-01
影响因子：
5.3
通讯作者：
Yamada, N
中科院分区：
文献类型：
--
作者：
Inoue, N;Shimano, H;Yamada, N
固醇调节元件结合蛋白（SREBP）是一种膜结合的转录因子，调节脂质合成基因。与调节正常细胞中细胞胆固醇水平的SREBP-2相反，SREBP-1a在活跃生长的细胞中高度表达，并激活参与脂质合成的基因的整个程序，如胆固醇，脂肪酸，甘油三酯和磷脂。以前，SREBP-1a的这种有效活性的生理相关性被认为调节响应细胞生长的膜脂质的供应。在这里，我们表明，核SREBP-1a和SREBP-2直接结合到一个新的SREBP结合位点的p21（WAF 1/CIP 1）基因的启动子，主要的细胞周期蛋白依赖性激酶抑制剂，并强烈激活其启动子活性。只有SREBP-1a亚型始终引起p21的诱导。在mRNA和蛋白质水平上。转基因小鼠肝脏的集落形成试验和多倍性表明p21的激活。SREBP-1a可抑制细胞生长。在脂质剥夺条件下内源性SREBP的激活与p21 mRNA和蛋白的诱导相关。在SREBP-1敲除小鼠中，p21的表达降低。这些数据表明SREBP-1a在p21调节中的生理作用。p21作为一个新的SREBP靶点的鉴定可能涉及脂质合成和细胞生长之间联系的新范式。
Sterol regulatory element-binding proteins (SREBPs) are membrane-bound transcription factors that regulate lipid synthetic genes. In contrast to SREBP-2, which regulates cellular cholesterol level in normal cells, SREBP-1a is highly expressed in actively growing cells and activates entire programs of genes involved in lipid synthesis such as cholesterol, fatty acids, triglycerides, and phospholipids. Previously, the physiological relevance of this potent activity of SREBP-1a has been thought to regulate the supply of membrane lipids in response to cell growth. Here we show that nuclear SREBP-1a and SREBP-2 bind directly to a novel SREBP binding site in the promoter of the p21(WAF1/CIP1) gene, the major cyclin-dependent kinase inhibitor, and strongly activate its promoter activity. Only the SREBP-1a isoform consistently causes induction of p21. at both the mRNA and protein levels. Colony formation assays and polyploidy of livers from transgenic mice suggest that activation of p21. by SREBP-1a could inhibit cell growth. Activation of endogenous SREBPs in lipid deprivation conditions was associated with induction of p21 mRNA and protein. Expression of p21 was reduced in SREBP-1 null mice. These data suggest a physiological role of SREBP-1a in p21 regulation. Identification of p21 as a new SREBP target might implicate a new paradigm in the link between lipid synthesis and cell growth.