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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    ABSTRACT: From C. elegans to mammals (including humans), nutrition and energy metabolism significantly influence reproduction. At the cellular level, some detectors of energy status indicate whether energy reserves are abundant (obesity), or poor (diet restriction). One of these detectors is AMPK (5' AMP-activated protein kinase), a protein kinase activated by ATP deficiency but also by several natural substances such as polyphenols or synthetic molecules like metformin, used in the treatment of insulin resistance. AMPK is expressed in muscle and liver, but also in the ovary and testis. This review focuses on the main effects of AMPK identified in gonadal cells. We describe the role of AMPK in gonadal steroidogenesis, in proliferation and survival of somatic gonadal cells and in the maturation of oocytes or spermatozoa. We discuss also the role of AMPK in germ and somatic cell interactions within the cumulus-oocyte complex and in the blood testis barrier. Finally, the interface in the gonad between AMPK and modification of metabolism is reported and discussion about the role of AMPK on fertility, in regards to the treatment of infertility associated with insulin resistance (male obesity, polycystic ovary syndrome).
    Frontiers in Neuroscience 07/2015; 9:235. DOI:10.3389/fnins.2015.00235 · 3.66 Impact Factor
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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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    ABSTRACT: Experimental evidence shows that telomere shortening induces mitochondrial damage but so far studies in humans are scarce. Here, we investigated the association between leukocyte telomere length (LTL) and mitochondrial DNA (mtDNA) content in elderly and explored possible intermediate mechanisms by determining the gene expression profile of candidate genes in the telomere-mitochondrial axis of ageing. Among 166 non-smoking elderly, LTL, leukocyte mtDNA content and expression of candidate genes: sirtuin1 (SIRT1), tumor protein p53 (TP53), peroxisome proliferator-activated receptor γ-coactivator1α (PGC-1α), peroxisome proliferator-activated receptor γ-coactivator1β (PGC-1β), nuclear respiratory factor 1 (NRF1) and nuclear factor, erythroid 2 like 2 (NRF2), using a quantitave real time polymerase chain assay (qPCR). Statistical mediation analysis was used to study intermediate mechanisms of the telomere-mitochondrial axis of ageing. LTL correlated with leukocyte mtDNA content in our studied elderly (r=0.23, p=0.0047). SIRT1 gene expression correlated positively with LTL (r=0.26, p=0.0094) and leukocyte mtDNA content (r=0.43, p<0.0001). The other studied candidates showed significant correlations in the telomere-mitochondrial interactome but not independent from SIRT1. SIRT1 gene expression was estimated to mediate 40% of the positive association between LTL and leukocyte mtDNA content. The key finding of our study was that SIRT1 expression plays a pivotal role in the telomere-mitochondrial interactome. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Mechanisms of Ageing and Development 02/2015; 145. DOI:10.1016/j.mad.2015.02.003 · 3.40 Impact Factor
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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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    ABSTRACT: Aging hematopoietic stem cells (HSCs) exhibit defective lineage specification that is thought to be central to increased incidence of myeloid malignancies and compromised immune competence in the elderly. Mechanisms underlying these age-related defects remain largely unknown. We show that the deacetylase Sirtuin (SIRT)1 is required for homeostatic HSC maintenance. Differentiation of young SIRT1-deleted HSCs is skewed toward myeloid lineage associated with a significant decline in the lymphoid compartment, anemia, and altered expression of associated genes. Combined with HSC accumulation of damaged DNA and expression patterns of age-linked molecules, these have striking overlaps with aged HSCs. We further show that SIRT1 controls HSC homeostasis via the longevity transcription factor FOXO3. These findings suggest that SIRT1 is essential for HSC homeostasis and lineage specification. They also indicate that SIRT1 might contribute to delaying HSC aging.
    Stem Cell Reports 07/2014; 3(1). DOI:10.1016/j.stemcr.2014.04.015 · 5.37 Impact Factor
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