S-adenosylmethionine regulates cytoplasmic HuR via AMP-activated kinase
S-adenosylmethionine regulates cytoplasmic HuR via AMP-activated kinase
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DOI：
10.1053/j.gastro.2006.04.019
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发表时间：
2006-07-01
期刊：
影响因子：
29.4
通讯作者：
Mato, Jose M.
中科院分区：
文献类型：
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作者：
Martinez-Chantar, Maria L.;Vazquez-Chantada, Mercedes;Mato, Jose M.
背景和目标：肝损伤后，肝S-腺苷甲硫氨酸（SAM）含量降低，这种分子对肝细胞增殖的阻断作用被释放，促进肝再生。SAM的这种活性对于正常的肝功能是重要的，因为肝SAM缺陷的小鼠显示异常的肝再生并发展肝细胞癌。SAM如何调节肝细胞生长尚不清楚，但由于SAM阻断肝细胞生长因子（HGF）包括细胞周期蛋白D1的表达和DNA合成，而不影响HGF诱导的细胞外信号调节激酶磷酸化，丝裂原活化蛋白激酶（MAPK）途径可能不是目标。方法：观察SAM对HGF、AICAR和SAM处理的大鼠肝细胞AMPK、HuR定位的影响。结果如下：我们在这里显示，肝细胞生长因子和5-氨基咪唑-4-甲酰胺核苷（AICAR），一个激活剂的AMP激活的蛋白激酶（AMPK），诱导磷酸化的AMPK在肝细胞和SAM阻断这一过程。我们还表明，HGF和AICAR诱导的AMPK激活刺激运输从细胞核到细胞质的HuR，RNA结合蛋白，增加半衰期的目标mRNA，如细胞周期蛋白A2，SAM块这一过程。我们发现，在肝细胞中，AICAR增加HuR与细胞周期蛋白A2信使RNA（mRNA）的结合以及该mRNA的表达和稳定性，SAM阻断这些事件。因此，我们发现AICAR诱导肝细胞增殖，SAM阻断这种作用。最后，我们发现肝脏AMPK磷酸化，细胞质HuR，HuR与HuR靶mRNA的结合以及这些mRNA的稳态水平在缺乏肝脏SAM的敲除小鼠中增加。结论：我们的研究结果产生了新的见解SAM抑制肝细胞周期进程的机制。
Background & Aims: After liver injury, hepatic S-adenosylmethionine (SAM) content decreases, and the blockage this molecule imposes on hepatocyte proliferation is released, facilitating liver regeneration. This activity of SAM is important for normal liver function because mice deficient in hepatic SAM display abnormal liver regeneration and develop hepatocellular carcinoma. How SAM regulates hepatocyte growth is unclear, but because SAM blocks hepatocyte growth factor (HGF)-included cyclin D1 expression and DNA synthesis without affecting HGF-induced extracellular signal-regulated kinase phosphorylation, the mitogen-activated protein kinase (MAPK) pathway is probably not the target. Methods: The effects of SAM on AMPK, HuR localization were assessed in rat hepatocytes after HGF, AICAR, and SAM treatment. Results: We show here that HGF and 5-aminoimidazole-4-carboxamide-riboside (AICAR), an activator of AMP-activated protein kinase (AMPK), induce the phosphorylation of AMPK in hepatocytes and that SAM blocks this process. We also show that HGF-and AICAR-induced AMPK activation stimulate the transport from nucleus to cytoplasm of HuR, an RNA-binding protein that increases the half-life of target mRNA such as cyclin A2, and that SAM blocks this process. We found that, in hepatocytes, AICAR increases HuR binding to cyclin A2 messenger RNA (mRNA) as well as the expression and stability of this mRNA and that SAM blocks these events. Consistently, we found that AICAR induces hepatocyte proliferation and that SAM blocks this effect. Finally, we found that liver AMPK phosphorylation, cytoplasmic HuR, and binding of HuR to HuR-target mRNA and the steady-state levels of these mRNA are increased in knockout mice deficient in hepatic SAM. Conclusions: Our results yield novel insights about the mechanism by which SAM inhibits cell-cycle progression in the liver.