Journal article
A single-nucleotide variation in a p53-binding site affects nutrient-sensitive human SIRT1 expression
Human molecular genetics, Vol.19(21), pp.4123-4133
11/01/2010
DOI: 10.1093/hmg/ddq331
PMCID: PMC2951863
PMID: 20693263
Abstract
The SIRTUIN1 (SIRT1) deacetylase responds to changes in nutrient availability and regulates mammalian physiology and metabolism. Human and mouse SIRT1 are transcriptionally repressed by p53 via p53 response elements in their proximal promoters. Here, we identify a novel p53-binding sequence in the distal human SIRT1 promoter that is required for nutrient-sensitive SIRT1 transcription. In addition, we show that a common single-nucleotide (C/T) variation in this sequence affects nutrient deprivation-induced SIRT1 transcription, and calorie restriction-induced SIRT1 expression. The p53-binding sequence lies in a region of the SIRT1 promoter that also binds the transcriptional repressor Hypermethylated-In-Cancer-1 (HIC1). Nutrient deprivation increases occupancy by p53, while decreasing occupancy by HIC1, of this region of the promoter. HIC1 and p53 compete with each other for promoter occupancy. In comparison with the T variation, the C variation disrupts the mirror image symmetry of the p53-binding sequence, resulting in decreased binding to p53, decreased nutrient sensitivity of the promoter and impaired calorie restriction-stimulated tissue expression of SIRT1 and SIRT1 target genes
AMPKα2
and
PGC-1β
. Thus, a common SNP in a novel p53-binding sequence in the human SIRT1 promoter affects nutrient-sensitive SIRT1 expression, and could have a significant impact on calorie restriction-induced, SIRT1-mediated, changes in human metabolism and physiology.
Details
- Title: Subtitle
- A single-nucleotide variation in a p53-binding site affects nutrient-sensitive human SIRT1 expression
- Creators
- Asma Naqvi - Cardiovascular InstituteTimothy A Hoffman - Cardiovascular InstituteJeremy DeRicco - Cardiovascular InstituteAjay Kumar - Cardiovascular InstituteCuk-Seong Kim - Cardiovascular InstituteSaet-Byel Jung - Cardiovascular InstituteTohru Yamamori - Cardiovascular InstituteYoung-Rae Kim - Cardiovascular InstituteFardeen Mehdi - Cardiovascular InstituteSantosh Kumar - Cardiovascular InstituteTuomo Rankinen - Pennington Biomedical Research CenterEric Ravussin - Pennington Biomedical Research CenterKaikobad Irani - Cardiovascular Institute
- Resource Type
- Journal article
- Publication Details
- Human molecular genetics, Vol.19(21), pp.4123-4133
- Publisher
- Oxford University Press
- DOI
- 10.1093/hmg/ddq331
- PMID
- 20693263
- PMCID
- PMC2951863
- ISSN
- 0964-6906
- eISSN
- 1460-2083
- Language
- English
- Date published
- 11/01/2010
- Academic Unit
- Cardiovascular Medicine; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
- Record Identifier
- 9984047761802771
Metrics
21 Record Views