Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice

By Hwei-Ling Cheng, R. Mostoslavsky, Shinichi Saito, J. Manis, Yansong Gu, Parin Patel, R. Bronson, E. Appella, F. Alt, Katrin F. Chua. Proceedings of the National Academy of Sciences of the United States of America, 2003

1,125 citations recorded by the source corpus.

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.

Subfields: Geriatrics and Gerontology, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/5f3e9be5e16c48eaaa0bc3be42310e6dd3ce6c27

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Geriatrics and Gerontology

1. L. Guarente
2. D. Sinclair
3. M. Haigis
4. E. Verdin
5. Bor Luen Tang
6. E. Seto
7. R. Mostoslavsky
8. V. Longo

In Molecular Biology

1. L. Guarente
2. E. Verdin
3. E. Seto
4. W. Gu
5. M. Haigis
6. D. Sinclair
7. Bor Luen Tang
8. Xiang-Jiao Yang

In Oncology

1. E. Seto
2. W. Gu
3. Bor Luen Tang
4. J. Campisi
5. Xiang-Jiao Yang
6. L. Guarente
7. Adam Freund
8. D. Sinclair

Citations in the corpus

• Sirtuins: critical regulators at the crossroads between cancer and aging (2007, background): “In response to stress signals, p53 is acetylated at multiple lysines, which enhances its activity and stability (Barlev et al., 2001). p53 is deacetylated on lysine 382 (K379 in mouse p53) both by SIRT1 and HDAC1 (Luo et al., 2001; Vaziri et al., 2001; Cheng et al., 2003). p53 recruitment of HATs an”
• Human HDAC1 and HDAC2 function in the DNA-damage response to promote DNA non-homologous end-joining (2010, neutral): “5f ; analysis of p53 acetylation, a known sirtuin targe”
• Acetylation of tau inhibits its degradation and contributes to tauopathy. (2010, positive): “To delete SIRT1, we crossedSIRT1 miceonanoutbredbackground,whichpartially rescued the embryonic lethality of SIRT1 null mice on the inbred background (Cheng et al., 2003).”
• Sirtuins in aging and age-related disease. (2006, background): “In mammals, considerable evidence exists to suggest that the tumor suppressor p53 is a target for deacetylation by Sirt1 (Cheng et al., 2003).”
• A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy (2008, positive): “To confirm these results in vivo, we used our published line of Sirt1 knockout mice (15).”
• Modulation of NF‐κB‐dependent transcription and cell survival by the SIRT1 deacetylase (2004, background): “The EMBO Journal VOL 23 | NO 12 | 2004 &2004 European Molecular Biology Organization2376 Cheng et al, 2003).”
• Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins. (2005, background): “, 2003; Takata and Ishikawa, 2003) and Sirt1 knockout mice (Cheng et al., 2003; McBurney et al., 2003b) suggest its roles in mammalian development and differentiation.”
• SIRT1 controls endothelial angiogenic functions during vascular growth. (2007, background): “…the early postnatal lethality of SIRT1-null mice precluded further analysis of potential vascular defects during postnatal angiogenesis (Cheng et al. 2003), we analyzed mice carrying a “floxed” SIRT1 allele (SIRT1flox), in which exon 4 encoding for 51 amino acids of the conserved SIRT1…”
• Mammalian sirtuins--emerging roles in physiology, aging, and calorie restriction. (2006, background): “Outbred SIRT1 KO animals can survive into adulthood, but demonstrate a severe phenotype, including small size, delayed bone mineralization , defective skeletal closure, delayed eyelid opening , and sterility (Cheng et al. 2003; McBurney et al. 2003; Lemieux et al. 2005).”
• Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice (2008, neutral): “Furthermore, these mutant mice also contained distinct targeted mutations, i.e., a replacement of exons 5 and 6 with a hygromycin gene (McBurney et al., 2003), a deletion of exon 4 (Cheng et al., 2003), or a deletion of exons 5 and 6 (this study) using the Cre/loxP-mediated approach.”