The yeast Sir2 protein mediates chromatin silencing through an intrinsic NAD-dependent histone deacetylase activity. Sir2 is a conserved protein and was recently shown to regulate lifespan extension both in budding yeast and worms. Here, we show that SIRT1, the human Sir2 homolog, is recruited to the promyelocytic leukemia protein (PML) nuclear bodies of mammalian cells upon overexpression of either PML or oncogenic Ras (Ha-rasV12). SIRT1 binds and deacetylates p53, a component of PML nuclear bodies, and it can repress p53-mediated transactivation. Moreover, we show that SIRT1 and p53 co-localize in nuclear bodies upon PML upregulation. When overexpressed in primary mouse embryo fibroblasts (MEFs), SIRT1 antagonizes PML-induced acetylation of p53 and rescues PML-mediated premature cellular senescence. Taken together, our data establish the SIRT1 deacetylase as a novel negative regulator of p53 function capable of modulating cellular senescence.
|Titolo:||Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence|
PELICCI, PIER GIUSEPPE (Penultimo)
|Parole Chiave:||Animals; Tumor Suppressor Protein p53; Testis; HeLa Cells; Histone Deacetylases; Recombinant Proteins; Humans; Sirtuins; Sirtuin 1; Mice; Sirtuin 2; Transcriptional Activation; Tumor Suppressor Proteins; Fibroblasts; Silent Information Regulator Proteins, Saccharomyces cerevisiae; Neoplasm Proteins; Transcription Factors; Nuclear Proteins; Transfection; Cell Aging; Trans-Activators; Cell Line; Male|
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
|Data di pubblicazione:||15-mag-2002|
|Digital Object Identifier (DOI):||10.1093/emboj/21.10.2383|
|Appare nelle tipologie:||01 - Articolo su periodico|