SIRT1 Acts as a Nutrient-sensitive Growth Suppressor and Its Loss Is Associated with Increased AMPK and Telomerase Activity
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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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Nutrient-sensing pathways SIRT1, AMPK and FoxO may be molecular effectors of calorie restriction's benefits on stem cell activity.
“Signaling pathways related to nutrient sensing and uptake, such as SIRT1, AMPK and FoxO, may represent molecular effectors of the benefits of CR on stem cell activity113,114, although a complete understanding of how CR affects stem cell function must await further studies.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [113]
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- Authors
- Narala, S. R., Allsopp, R. C., Wells, T. B., Zhang, G., Prasad, P., Coussens, M. J., Rossi, D. J., Weissman, I. L., & Vaziri, H.
- Affiliations
- University of Toronto (CA)
- University of Hawaiʻi at Mānoa (US)
- Institute for Stem Cell Biology and Regenerative Medicine (US)
- Venue
- Molecular Biology of the Cell
- Published
- 2008-03
- Volume
- 19
- Issue
- 3
- Pages
- 1210-1219
- ISSN
- 1059-1524 (ISSN-L)
- 1939-4586
- PMC
- PMC2262963
- OpenAlex
- W2145650048
- Cited by
- 106
- References
- 64
- Citations by year
- 2024: 1 · 2023: 4 · 2022: 1 · 2021: 5 · 2020: 2 · 2019: 1 · 2018: 6 · 2017: 4 · 2016: 3 · 2015: 9 · 2014: 11 · 2013: 9 · 2012: 8
- FWCI
- 5.71
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Biology of the Cell (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Canadian Institutes of Health Research
- National Center for Research Resources (P20RR16467-05, P20RR016467)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- SIRT1, NAD+-dependent deacetylase, growth inhibition, nutrient sensing, AMPK, telomerase activity, hTERT, cell immortalization, hematopoietic stem cells, glucose limitation, lifespan, NAD+ metabolism, shRNA knockdown
- MeSH terms
- Animals, Cell Line, Cell Survival, Food, Glucose, Hematopoietic Stem Cells, Humans, Multienzyme Complexes, Protein Serine-Threonine Kinases, Telomerase, Sirtuins, Cell Proliferation, Mice, AMP-Activated Protein Kinases, Sirtuin 1
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