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 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.
Narala
Swami R
SR
Ontario Cancer Institute, Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G-2M9, Canada.
Allsopp
Richard C
RC
Wells
Trystan B
TB
Zhang
Guanglei
G
Prasad
Prerna
P
Coussens
Matthew J
MJ
Rossi
Derrick J
DJ
Weissman
Irving L
IL
Vaziri
Homayoun
H
D055372:AMP-Activated Protein Kinases; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D005502:Food; D005947:Glucose / Q000172:deficiency; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D051379:Mice; D009097:Multienzyme Complexes / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D056564:Sirtuin 1; D037761:Sirtuins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000378:metabolism*
D009097:Multienzyme Complexes; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D019098:Telomerase; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D037761:Sirtuins; D005947:Glucose