SIRT1 acts as a nutrient-sensitive growth suppressor and its loss is associated with increased AMPK and telomerase activity
SIRT1 acts as a nutrient-sensitive growth suppressor and its loss is associated with increased AMPK and telomerase activity
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DOI：
10.1091/mbc.e07-09-0965
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发表时间：
2008-03-01
影响因子：
3.3
通讯作者：
Vaziri, Homayoun
中科院分区：
文献类型：
--
作者：
Narala, Swami R.;Allsopp, Richard C.;Vaziri, Homayoun
SIRT1是酿酒酵母中SIR2的哺乳动物同源物，是一种参与调节寿命的NAD依赖性脱乙酰酶。通过设计有效的短发夹RNA和沉默的shRNA抗性突变体SIRT1的遗传定义的系统中，我们表明，有效抑制SIRT1端粒酶永生化的人类细胞在正常和营养限制条件下增强细胞生长。从SIRT1缺陷小鼠获得的造血干细胞也显示出生长能力增加和对生长因子的依赖性降低。与此相一致，SIRT1抑制与人类细胞中端粒酶活性的增加有关。我们还观察到在葡萄糖限制条件下SIRT1抑制时AMPK水平显著增加。尽管SIRT1抑制与hTERT协同促进细胞生长，但单独过表达或抑制SIRT1对人二倍体成纤维细胞的寿命没有影响。我们的发现挑战了某些模型，并将营养传感酶与永生化过程联系起来。此外，他们表明，在某些细胞谱系中，SIRT1可以作为生长抑制基因。
SIRT1, the mammalian homolog of SIR2 in Saccharomyces cerevisiae, is an NAD-dependent deacetylase implicated in regulation of lifespan. By designing effective short hairpin RNAs and a silent shRNA-resistant mutant SIRT1 in a genetically defined system, we show that efficient inhibition of SIRT1 in telomerase-immortalized human cells enhanced cell growth under normal and nutrient limiting conditions. Hematopoietic stem cells obtained from SIRT1-deficient mice also showed increased growth capacity and decreased dependency on growth factors. Consistent with this, SIRT1 inhibition was associated with increased telomerase activity in human cells. We also observed a significant increase in AMPK levels up on SIRT1 inhibition under glucose limiting conditions. Although SIRT1 suppression cooperated with hTERT to promote cell growth, either overexpression or suppression of SIRT1 alone had no effect on life span of human diploid fibroblasts. Our findings challenge certain models and connect nutrient sensing enzymes to the immortalization process. Furthermore, they show that in certain cell lineages, SIRT1 can act as a growth suppressor gene.