title: Poly(ADP-ribosyl)ation of p53 induces gene-specific transcriptional repression of MTA1.
abstract: The metastasis-associated protein 1 (MTA1) is overexpressed in various human cancers and is closely connected with aggressive phenotypes; however, little is known about the transcriptional regulation of the MTA1 gene. This study identified the MTA1 gene as a target of p53-mediated transrepression. The MTA1 promoter contains two putative p53 response elements (p53REs), which were repressed by the p53-inducing drug 5-fluorouracil (5-FU). Notably, 5-FU treatment decreased MTA1 expression only in p53 wild-type cells. p53 and histone deacetylases 1/2 were recruited, and acetylation of H3K9 was decreased on the promoter region including the p53REs after 5-FU treatment. Proteomics analysis of the p53 repressor complex, which was pulled down by the MTA1 promoter, revealed that the poly(ADP-ribose) polymerase 1 (PARP-1) was part of the complex. Interestingly, p53 was poly(ADP-ribose)ylated by PARP-1, and the p53-mediated transrepression of the MTA1 gene required poly(ADP-ribose)ylation of p53. In summary, we report a novel function for poly(ADP-ribose)ylation of p53 in the gene-specific regulation of the transcriptional mode of p53 on the promoter of MTA1.
authors.affiliation: College of Pharmacy and Bio-MAX Institute, Seoul National University, Seoul, Republic of Korea.
authors.forename: M-H
authors.initials: MH
authors.lastname: Lee
authors.forename: H
authors.initials: H
authors.lastname: Na
authors.forename: E-J
authors.initials: EJ
authors.lastname: Kim
authors.forename: H-W
authors.initials: HW
authors.lastname: Lee
authors.forename: M-O
authors.initials: MO
authors.lastname: Lee
mesh_terms: D000818:Animals; D002460:Cell Line; D005347:Fibroblasts / Q000378:metabolism; D005472:Fluorouracil / Q000494:pharmacology; D005786:Gene Expression Regulation; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000235:genetics / Q000378:metabolism; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D061986:MCF-7 Cells / Q000187:drug effects; D051379:Mice; D000071137:Poly (ADP-Ribose) Polymerase-1; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D020218:Response Elements; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C089320:MTA1 protein, human; D012097:Repressor Proteins; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D011064:Poly Adenosine Diphosphate Ribose; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C110550:HDAC1 protein, human; C533423:HDAC2 protein, human; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases; D005472:Fluorouracil