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MBC in Press, published online ahead of print January 9, 2008
Mol. Biol. Cell 10.1091/mbc.E07-09-0965

A more recent version of this article appeared on March 1, 2008
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Submitted on September 25, 2007
Revised on December 1, 2007
Accepted on December 27, 2007

SIRT1 Acts as a Nutrient-sensitive Growth Suppressor and its Loss is Associated with Increased AMPK and Telomerase Activity

Swami R. Narala,* Richard C. Allsopp,{dagger} Trystan B. Wells,* Guanglei Zhang,* Prerna Prasad,{dagger} Matthew J. Coussens,{dagger} Derrick J. Rossi,{ddagger} Irving L. Weissman,{ddagger} and Homayoun Vaziri*

*Ontario Cancer Institute, Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G-2M9, Canada; {ddagger}Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, 94305; {dagger}Institute for Biogenesis Research, University of Hawaii, Honolulu, HI, 96813

Monitoring Editor: Wendy Bickmore

SIRT1, the mammalian homolog of SIR2 in S. cerevisiae, is an NAD-dependent deacetylase implicated in regulation of lifespan. By designing effective shRNAs 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.

Address correspondence to: Homayoun Vaziri (vaziri{at}oci.utoronto.ca)






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