SIRT1 acts as a nutrient-sensitive growth suppressor and its loss is associated with increased AMPK and telomerase activity

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 t...

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Published in:Molecular biology of the cell 2008-03, Vol.19 (3), p.1210-1219
Main Authors: Narala, Swami R, Allsopp, Richard C, Wells, Trystan B, Zhang, Guanglei, Prasad, Prerna, Coussens, Matthew J, Rossi, Derrick J, Weissman, Irving L, Vaziri, Homayoun
Format: Article
Language:English
Subjects:
AMP-Activated Protein Kinases
Animals
Cell Line
Cell Proliferation
Cell Survival
Food
Glucose - deficiency
Hematopoietic Stem Cells - cytology
Humans
Mice
Multienzyme Complexes - metabolism
Protein-Serine-Threonine Kinases - metabolism
Sirtuin 1
Sirtuins - antagonists & inhibitors
Sirtuins - deficiency
Sirtuins - metabolism
Telomerase - antagonists & inhibitors
Telomerase - metabolism
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Summary: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.
ISSN:1059-1524
1939-4586
DOI:10.1091/mbc.E07-09-0965