title: ATR and GADD45alpha mediate HIV-1 Vpr-induced apoptosis.
abstract: The human immunodeficiency virus type-1 (HIV-1) accessory gene vpr encodes a conserved 96-amino-acid protein that is necessary and sufficient for the HIV-1-induced block of cellular proliferation. Expression of vpr in CD4+ lymphocytes results in G2 arrest, followed by apoptosis. In a previous study, we identified the ataxia telangiectasia-mutated (ATM) and Rad3-related protein (ATR) as a cellular factor that mediates Vpr-induced cell cycle arrest. In the present study, we report that the breast cancer-associated protein-1 (BRCA1), a known target of ATR, is activated in the presence of Vpr. In addition, the gene encoding the growth arrest and DNA damage-45 protein alpha (GADD45alpha), a known transcriptional target of BRCA1, is upregulated by Vpr in an ATR-dependent manner. We demonstrate that RNAi-mediated silencing of either ATR or GADD45alpha leads to nearly complete suppression of the proapoptotic effect of Vpr. Our results support a model in which Vpr-induced apoptosis is mediated via ATR phosphorylation of BRCA1, and consequent upregulation of GADD45alpha.
authors.affiliation: Department of Pathology, Division of Cellular Biology and Immunology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Andersen
authors.forename: E S
authors.initials: ES
authors.lastname: Zimmerman
authors.forename: J L
authors.initials: JL
authors.lastname: DeHart
authors.forename: S
authors.initials: S
authors.lastname: Murala
authors.forename: O
authors.initials: O
authors.lastname: Ardon
authors.forename: J
authors.initials: J
authors.lastname: Blackett
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.forename: V
authors.initials: V
authors.lastname: Planelles
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D064007:Ataxia Telangiectasia Mutated Proteins; D019313:BRCA1 Protein / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D061945:Caspase Inhibitors; D018797:Cell Cycle Proteins / Q000378:metabolism*; D016195:G2 Phase / Q000502:physiology; D016336:Gene Products, vpr / Q000378:metabolism*; D015497:HIV-1 / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000378:metabolism; D054325:vpr Gene Products, Human Immunodeficiency Virus; D000097642:GADD45 Proteins
chemical_list: D064007:Ataxia Telangiectasia Mutated Proteins; D019313:BRCA1 Protein; D061945:Caspase Inhibitors; D018797:Cell Cycle Proteins; D016336:Gene Products, vpr; D020928:Mitogen-Activated Protein Kinases; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D012694:Serine; D054325:vpr Gene Products, Human Immunodeficiency Virus; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C576597:ATR protein, human