title: The ARF/oncogene pathway activates p53 acetylation within the DNA binding domain.
abstract: Stabilization of the p53 tumor suppressor is a critical event in the response to various forms of cellular stress. Two distinct signaling pathways are thought to lead to this stabilization, depending on the type of cellular stress encountered. Genotoxic stress, such as chromosomal breaks or lesions induced by chemotherapeutic agents, result in the activation of the well-characterized DNA damage response pathway. Conversely, cellular stress that results from the aberrant activation of oncogenes triggers p53 stabilization via the induction of the p19ARF pathway. While activation of the DNA damage pathway ultimately causes a complex array of post-translational modifications on p53, few if any modifications have been demonstrated to occur following activation of the p19ARF pathway. We and others have recently identified a novel modification on p53, acetylation of lysine 120 within the DNA binding domain. This acetylation event is eliminated by tumor-derived mutations in p53 and its presence is required for the tumor suppressor apoptotic function of p53. We demonstrate here that both the DNA damage response pathway and the p19ARF/oncogene stress pathway induce the acetylation of p53 at lysine 120.
authors.affiliation: Biomedical Graduate Studies, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Hestia
authors.initials: H
authors.lastname: Mellert
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Sykes
authors.forename: Maureen E
authors.initials: ME
authors.lastname: Murphy
authors.forename: Steven B
authors.initials: SB
authors.lastname: McMahon
mesh_terms: D000107:Acetylation; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000502:physiology*; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D004318:Doxycycline / Q000494:pharmacology; D016158:Genes, p53; D051548:Histone Acetyltransferases / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D000074443:Lysine Acetyltransferase 5; D051379:Mice; D010714:Phosphatidylethanolamines; D011485:Protein Binding; D011499:Protein Processing, Post-Translational / Q000502:physiology; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000502:physiology; D013312:Stress, Physiological / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism*
chemical_list: C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D010714:Phosphatidylethanolamines; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; C100004:transfectACE; D004247:DNA; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; C496552:KAT8 protein, human; D000074443:Lysine Acetyltransferase 5; D008239:Lysine; D004318:Doxycycline