ArticleProceedings of the National Academy of Sciences of the United States of America2003
Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2003. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 592 papers.
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Who cites it
592 citing papers in PubMed, 1,087 citations in OpenAlex.
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- The GPR4 antagonist NE 52-QQ57 prevents ox-LDL-induced cellular senescence by promoting the expression of SIRT1.Genes & genomics · 2025Article
- Mito-TEMPO Mitigates Fibromyalgia Induced by Reserpine in Rats: Orchestration Between SIRT1, Mitochondrial Dynamics, Endoplasmic Reticulum and miRNA-320.Neurochemical research · 2025Article
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- Role of sirtuins in obesity and osteoporosis: molecular mechanisms and therapeutic targets.Cell communication and signaling : CCS · 2025Review
- SIRT1: The first key to unlocking the mystery of cardiovascular diseases.Frontiers in pharmacology · 2025Review
- Article
532 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
SIRT1 is a mammalian homolog of the Saccharomyces cerevisiae chromatin silencing factor Sir2. Dominant-negative and overexpression studies have implicated a role for SIRT1 in deacetylating the p53 tumor suppressor protein to dampen apoptotic and cellular senescence pathways. To elucidate SIRT1 function in normal cells, we used gene-targeted mutation to generate mice that express either a mutant SIRT1 protein that lacks part of the catalytic domain or has no detectable SIRT1 protein at all. Both types of SIRT1 mutant mice and cells had essentially the same phenotypes. SIRT1 mutant mice were small, and exhibited notable developmental defects of the retina and heart, and only infrequently survived postnatally. Moreover, SIRT1-deficient cells exhibited p53 hyperacetylation after DNA damage and increased ionizing radiation-induced thymocyte apoptosis. In SIRT1-deficient embryonic fibroblasts, however, p53 hyperacetylation after DNA damage was not accompanied by increased p21 protein induction or DNA damage sensitivity. Together, our observations provide direct evidence that endogenous SIRT1 protein regulates p53 acetylation and p53-dependent apoptosis, and show that the function of this enzyme is required for specific developmental processes.
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