SirT1 fails to affect p53-mediated biological functions.
The SirT1 gene encodes a protein deacetylase that acts on a number of nuclear substrates. p53 was identified as a SirT1 substrate whose transcriptional activity was reported to be negatively regulated by SirT1-dependent deacetylation. We set out to determine whether developmental defects and perinatal lethality observed in SirT1-null mice were caused by p53 hyperactivity by creating mice deficient for both SirT1 and p53. Animals null for both proteins were smaller than normal at birth, had eyelid opening defects and died during the late prenatal and early postnatal periods, a phenotype indistinguishable from mice deficient for SirT1 alone. Upon re-examination of the role of SirT1 in modulating p53 activity, we found that while SirT1 interacts with p53, the SirT1 protein had little effect on p53-dependent transcription of transfected or endogenous genes and did not affect the sensitivity of thymocytes and splenocytes to radiation-induced apoptosis. These findings suggest that SirT1 does not affect many p53-mediated biological activities despite the fact that acetylated p53 has been shown to be a substrate for SirT1.
Kamel
Christopher
C
Ottawa Health Research Institute and Departments of Medicine and Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada K1H 8L6.
Abrol
Meena
M
Jardine
Karen
K
He
Xiaohong
X
McBurney
Michael W
MW
D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D003433:Crosses, Genetic; D004307:Dose-Response Relationship, Radiation; D005143:Eyelids / Q000033:anatomy & histology; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D011485:Protein Binding; D056564:Sirtuin 1; D037761:Sirtuins / Q000172:deficiency / Q000378:metabolism*; D013154:Spleen / Q000166:cytology / Q000528:radiation effects; D013534:Survival; D050378:T-Lymphocytes, Regulatory / Q000528:radiation effects; D015533:Transcriptional Activation / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D016159:Tumor Suppressor Protein p53; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D037761:Sirtuins