A transcription factor of lipid synthesis, sterol regulatory element-binding protein (SREBP)-1a causes G1 cell-cycle arrest after accumulation of cyclin-dependent kinase (cdk) inhibitors
A transcription factor of lipid synthesis, sterol regulatory element-binding protein (SREBP)-1a causes G1 cell-cycle arrest after accumulation of cyclin-dependent kinase (cdk) inhibitors
复制标题
DOI：
10.1111/j.1742-4658.2007.05973.x
复制
发表时间：
2007-09-01
期刊：
影响因子：
5.4
通讯作者：
Yamada, Nobuhiro
中科院分区：
文献类型：
--
作者：
Nakakuki, Masanori;Shimano, Hitoshi;Yamada, Nobuhiro
固醇调节元件结合蛋白（SREBP）-1a是一种独特的膜结合转录因子，在活跃生长的细胞中高度表达，并参与胆固醇、脂肪酸和磷脂的生物合成。由于哺乳动物细胞需要合成膜脂质用于细胞复制，因此SREBP-1a在细胞增殖中的功能相关性被认为是生物适应。然而，这种有效的脂质合成激活剂对细胞生长的影响从未被探索过。在这里，我们表明，诱导核SREBP-1a，而不是SREBP-2，完全抑制细胞生长的诱导型中国仓鼠卵巢（CHO）细胞系。生长抑制通过G（1）细胞周期停滞发生，这在具有核SREBP-1a瞬时表达的各种细胞类型中观察到。SREBP-1a引起细胞周期蛋白依赖性激酶（cdk）抑制剂如p27、p21和p16的积累，导致cdk 2和cdk 4活性降低和Rb蛋白磷酸化不足。与p21的反式激活相反，SREBP-1a通过抑制SKP 2和KPC 1增强蛋白质的稳定性来激活p27。在体内，SREBP-1a表达转基因小鼠的肝脏在部分肝切除术后表现出受损的再生。SREBP-1缺失小鼠胚胎成纤维细胞的细胞增殖率高于野生型细胞。SREBP-1a的意想不到的细胞生长抑制作用提供了一个新的范例，连接脂质合成和细胞生长。
Sterol regulatory element-binding protein (SREBP)-1a is a unique membrane-bound transcription factor highly expressed in actively growing cells and involved in the biosynthesis of cholesterol, fatty acids, and phospholipids. Because mammalian cells need to synthesize membrane lipids for cell replication, the functional relevance of SREBP-1a in cell proliferation has been considered a biological adaptation. However, the effect of this potent lipid-synthesis activator on cell growth has never been explored. Here, we show that induction of nuclear SREBP-1a, but not SREBP-2, completely inhibited cell growth in inducible Chinese hamster ovary (CHO) cell lines. Growth inhibition occurred through G(1) cell-cycle arrest, which is observed in various cell types with transient expression of nuclear SREBP-1a. SREBP-1a caused the accumulation of cyclin-dependent kinase (cdk) inhibitors such as p27, p21, and p16, leading to reduced cdk2 and cdk4 activities and hypophosphorylation of Rb protein. In contrast to transactivation of p21, SREBP-1a activated p27 by enhancing stabilization of the protein through inhibition of SKP2 and KPC1. In vivo, SREBP-1a-expressing livers of transgenic mice exhibited impaired regeneration after partial hepatectomy. SREBP-1-null mouse embryonic fibroblasts had a higher cell proliferation rate than wild-type cells. The unexpected cell growth-inhibitory role of SREBP-1a provides a new paradigm to link lipid synthesis and cell growth.