The phosphorylation-dependent regulation of nuclear SREBP1 during mitosis links lipid metabolism and cell growth.
The phosphorylation-dependent regulation of nuclear SREBP1 during mitosis links lipid metabolism and cell growth.
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DOI：
10.1080/15384101.2016.1220456
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发表时间：
2016-10-17
期刊：
影响因子：
--
通讯作者：
Ericsson J
中科院分区：
文献类型：
--
作者：
Bengoechea-Alonso MT;Ericsson J
SREBP转录因子是脂质代谢的主要调节因子。脂质代谢紊乱是现代社会面临的几个健康问题的核心，包括心血管疾病、肥胖和糖尿病。此外，脂质代谢在癌细胞生长中的作用也受到越来越多的关注。转录活性SREBP分子是不稳定的，并以磷酸化依赖的方式被Fbw7快速降解，Fbw7是一种泛素连接酶，针对几种细胞周期调节蛋白进行降解。我们之前已经证明活跃的SREBP1在有丝分裂期间是稳定的。我们现在已经描述了参与有丝分裂细胞中SREBP1稳定的机制。这一过程是由核分裂激酶Cdk1磷酸化SREBP1中特定丝氨酸残基所启动的。这个残基的磷酸化为一个独立的有丝分裂激酶Plk1创造了一个对接位点。Plk1在有丝分裂细胞中与核SREBP1相互作用，磷酸化该蛋白c端结构域的许多残基，包括SREBP1中靠近Fbw7对接位点的苏氨酸残基。Plk1对这些残基的磷酸化阻断了SREBP1和Fbw7之间的相互作用，并减弱了细胞分裂过程中核SREBP1依赖Fbw7的降解。SREBP1失活导致有丝分裂缺陷，表明SREBP1可以调节细胞分裂。我们认为在细胞分裂过程中核SREBP1的有丝分裂磷酸化和稳定提供了脂质代谢和细胞增殖之间的联系。因此，目前的研究为新兴假说提供了额外的支持，即srebp依赖性脂质代谢可能对细胞生长很重要。
The SREBP transcription factors are major regulators of lipid metabolism. Disturbances in lipid metabolism are at the core of several health issues facing modern society, including cardiovascular disease, obesity and diabetes. In addition, the role of lipid metabolism in cancer cell growth is receiving increased attention. Transcriptionally active SREBP molecules are unstable and rapidly degraded in a phosphorylation-dependent manner by Fbw7, a ubiquitin ligase that targets several cell cycle regulatory proteins for degradation. We have previously demonstrated that active SREBP1 is stabilized during mitosis. We have now delineated the mechanisms involved in the stabilization of SREBP1 in mitotic cells. This process is initiated by the phosphorylation of a specific serine residue in nuclear SREBP1 by the mitotic kinase Cdk1. The phosphorylation of this residue creates a docking site for a separate mitotic kinase, Plk1. Plk1 interacts with nuclear SREBP1 in mitotic cells and phosphorylates a number of residues in the C-terminal domain of the protein, including a threonine residue in close proximity of the Fbw7 docking site in SREBP1. The phosphorylation of these residues by Plk1 blocks the interaction between SREBP1 and Fbw7 and attenuates the Fbw7-dependent degradation of nuclear SREBP1 during cell division. Inactivation of SREBP1 results in a mitotic defect, suggesting that SREBP1 could regulate cell division. We propose that the mitotic phosphorylation and stabilization of nuclear SREBP1 during cell division provides a link between lipid metabolism and cell proliferation. Thus, the current study provides additional support for the emerging hypothesis that SREBP-dependent lipid metabolism may be important for cell growth.
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影响因子：
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影响因子：
50.3
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