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

Abstract

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.

Engineering cord blood to improve engraftment after cord blood transplant

“…Another method of blocking in vitro differentiation of EPCs is the use of a vitamin B3 analogue-NAM, which inhibits several key enzymes that require NAD+, including the sirtuin family of histone/protein deacetylases (such as SIRT1) that regulate several biological pathways involving cell adhesion, migration, proliferation and differentiation (55)(56)(57)(58)(59). In preclinical studies, ex vivo treatment of CB CD34 + cells with NAM and cytokines led to their robust expansion (60,61).…”

Sirtuin 1: A Target for Kidney Diseases

“…Overexpression of SIRT1 stimulated the AMPK phosphorylation (147), whereas shRNA-mediated SIRT1 knockdown reduced AMPK phosphorylation (148). However, these results might need further confirmation because other studies showed that the loss of SIRT1 was associated with increased AMPK (149).…”

Energy metabolism and energy-sensing pathways in mammalian embryonic and adult stem cell fate

“…In vitro differentiation of mouse ESCs into the hematopoietic lineage is defective in the absence of SIRT1 (Ou et al, 2011), yet adult mice lacking SIRT1 display virtually normal hematopoiesis (Leko et al, 2012;Narala et al, 2008). It is possible that other histone deacetylases compensate for loss of SIRT1 in adulthood, allowing the blood constituents to form properly after development, even in the absence of SIRT1.…”