Motoshima Hiroyuki, Goldstein Barry J, Igata Motoyuki, Araki Eiichi
Department of Metabolic Medicine, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 8554, Japan.
J Physiol. 2006 Jul 1;574(Pt 1):63-71. doi: 10.1113/jphysiol.2006.108324. Epub 2006 Apr 13.
AMPK is a serine/threonine protein kinase, which serves as an energy sensor in all eukaryotic cell types. Published studies indicate that AMPK activation strongly suppresses cell proliferation in non-malignant cells as well as in tumour cells. These actions of AMPK appear to be mediated through multiple mechanisms including regulation of the cell cycle and inhibition of protein synthesis, de novo fatty acid synthesis, specifically the generation of mevalonate as well as other products downstream of mevalonate in the cholesterol synthesis pathway. Cell cycle regulation by AMPK is mediated by up-regulation of the p53-p21 axis as well as regulation of TSC2-mTOR (mammalian target of rapamycin) pathway. The AMPK signalling network contains a number of tumour suppressor genes including LKB1, p53, TSC1 and TSC2, and overcomes growth factor signalling from a variety of stimuli (via growth factors and by abnormal regulation of cellular proto-oncogenes including PI3K, Akt and ERK). These observations suggest that AMPK activation is a logical therapeutic target for diseases rooted in cellular proliferation, including atherosclerosis and cancer. In this review, we discuss about exciting recent advances indicating that AMPK functions as a suppressor of cell proliferation by controlling a variety of cellular events in normal cells as well as in tumour cells.
AMPK是一种丝氨酸/苏氨酸蛋白激酶，在所有真核细胞类型中作为能量传感器发挥作用。已发表的研究表明，AMPK激活在非恶性细胞以及肿瘤细胞中均能强烈抑制细胞增殖。AMPK的这些作用似乎是通过多种机制介导的，包括细胞周期调控以及对蛋白质合成、从头脂肪酸合成（特别是甲羟戊酸的生成以及胆固醇合成途径中甲羟戊酸下游的其他产物）的抑制。AMPK对细胞周期的调控是通过p53 - p21轴的上调以及TSC2 - mTOR（雷帕霉素哺乳动物靶标）途径的调控来介导的。AMPK信号网络包含许多肿瘤抑制基因，包括LKB1、p53、TSC1和TSC2，并能克服来自多种刺激的生长因子信号传导（通过生长因子以及细胞原癌基因如PI3K、Akt和ERK的异常调控）。这些观察结果表明，AMPK激活对于包括动脉粥样硬化和癌症在内的源于细胞增殖的疾病而言是一个合理的治疗靶点。在本综述中，我们讨论了近期令人兴奋的进展，这些进展表明AMPK通过控制正常细胞以及肿瘤细胞中的各种细胞事件，发挥细胞增殖抑制因子的作用。
