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

Ontario Cancer Institute, Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G-2M9, Canada.
Molecular biology of the cell (Impact Factor: 4.47). 04/2008; 19(3):1210-9. DOI: 10.1091/mbc.E07-09-0965
Source: PubMed


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.

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    • "IRT1 is widely regarded as a critical regulator of energy homeostasis and is implicated in a wide variety of cellular processes including metabolic diseases , cancer , aging , and reproduction ( Bordone and Guarente , 2005 ; Brooks and Gu , 2009 ; Haigis and Sinclair , 2010 ) . Furthermore it is known to interact with AMPK ( Fulco et al . , 2008 ; Narala et al . , 2008 ; Canto and Auwerx , 2009 ) . We have recently provided evidence in the oocyte that α1AMPK could be involved in chromatin remodeling , because we observed an increase in acetylation of H3 histone in oocytes from α1AMPK knockout oocytes ( Bertoldo et al . , 2015 ) . This was correlated , as expected with a reduction in histone deacetylas"
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    • "Increases in SIRT1 were shown to stabilize PPARGC1A and, in turn, increase mitochondrial biogenesis and function (Yamamoto et al., 2007). Moreover, the positive impact of SIRT1 may also arise from its deacetylation and the inactivation of TP53, which may attenuate checkpoint responses and depress PPARGC1A expression (Narala et al., 2008). "
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    • "SIRT1 coordinates pluripotency , differentiation, and stress response in mouse embryonic stem cells (ESCs) (Han et al., 2008). Whether SIRT1 regulates adult stem cells particularly in the hematopoietic system has been a matter of debate (Leko et al., 2012; Li et al., 2012; Narala et al., 2008; Singh et al., 2013; Yuan et al., 2012). Despite recent advances in understanding SIRT1 regulation of malignant and stressed hematopoiesis , whether SIRT1 has any function in the control of adult HSC homeostasis or aging remains unknown. "
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