title: Sequential involvement of Cdk1, mTOR and p53 in apoptosis induced by the HIV-1 envelope.
abstract: Syncytia arising from the fusion of cells expressing the HIV-1-encoded Env gene with cells expressing the CD4/CXCR4 complex undergo apoptosis following the nuclear translocation of mammalian target of rapamycin (mTOR), mTOR-mediated phosphorylation of p53 on Ser15 (p53(S15)), p53-dependent upregulation of Bax and activation of the mitochondrial death pathway. p53(S15) phosphorylation is only detected in syncytia in which nuclear fusion (karyogamy) has occurred. Karyogamy is secondary to a transient upregulation of cyclin B and a mitotic prophase-like dismantling of the nuclear envelope. Inhibition of cyclin-dependent kinase-1 (Cdk1) prevents karyogamy, mTOR activation, p53(S15) phosphorylation and apoptosis. Neutralization of p53 fails to prevent karyogamy, yet suppresses apoptosis. Peripheral blood mononuclear cells from HIV-1-infected patients exhibit an increase in cyclin B and mTOR expression, correlating with p53(S15) phosphorylation and viral load. Cdk1 inhibition prevents the death of syncytia elicited by HIV-1 infection of primary CD4 lymphoblasts. Thus, HIV-1 elicits a pro-apoptotic signal transduction pathway relying on the sequential action of cyclin B-Cdk1, mTOR and p53.
authors.affiliation: Centre National de la Recherche Scientifique, UMR1599, Institut Gustave Roussy, 39 rue Camille-Desmoulins, F-94805 Villejuif, , France.
authors.forename: Maria
authors.initials: M
authors.lastname: Castedo
authors.forename: Thomas
authors.initials: T
authors.lastname: Roumier
authors.forename: Julià
authors.initials: J
authors.lastname: Blanco
authors.forename: Karine F
authors.initials: KF
authors.lastname: Ferri
authors.forename: Jordi
authors.initials: J
authors.lastname: Barretina
authors.forename: Lionel A
authors.initials: LA
authors.lastname: Tintignac
authors.forename: Karine
authors.initials: K
authors.lastname: Andreau
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Perfettini
authors.forename: Alessandra
authors.initials: A
authors.lastname: Amendola
authors.forename: Roberta
authors.initials: R
authors.lastname: Nardacci
authors.forename: Philip
authors.initials: P
authors.lastname: Leduc
authors.forename: Donald E
authors.initials: DE
authors.lastname: Ingber
authors.forename: Sabine
authors.initials: S
authors.lastname: Druillennec
authors.forename: Bernard
authors.initials: B
authors.lastname: Roques
authors.forename: Serge A
authors.initials: SA
authors.lastname: Leibovitch
authors.forename: Montserrat
authors.initials: M
authors.lastname: Vilella-Bach
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.forename: José A
authors.initials: JA
authors.lastname: Este
authors.forename: Nazanine
authors.initials: N
authors.lastname: Modjtahedi
authors.forename: Mauro
authors.initials: M
authors.lastname: Piacentini
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
mesh_terms: D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D017209:Apoptosis / Q000502:physiology*; D015704:CD4 Antigens / Q000235:genetics / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000473:pathology / Q000821:virology; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics; D002467:Cell Nucleus / Q000502:physiology* / Q000648:ultrastructure; D020869:Gene Expression Profiling; D015686:Gene Products, env / Q000502:physiology*; D015726:Giant Cells / Q000166:cytology; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy / Q000276:immunology; D015497:HIV-1 / Q000502:physiology*; D006367:HeLa Cells / Q000166:cytology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000821:virology; D046911:Macromolecular Substances; D008561:Membrane Fusion; D008928:Mitochondria / Q000502:physiology; D009363:Neoplasm Proteins / Q000502:physiology; D009685:Nuclear Envelope / Q000502:physiology / Q000648:ultrastructure; D010766:Phosphorylation; D010768:Phosphoserine / Q000737:chemistry; D011494:Protein Kinases / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D019718:Receptors, CXCR4 / Q000235:genetics / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000502:physiology*; D019562:Viral Load; D051028:bcl-2-Associated X Protein
chemical_list: C494826:BAX protein, human; D015704:CD4 Antigens; D018797:Cell Cycle Proteins; D015686:Gene Products, env; D046911:Macromolecular Substances; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D019718:Receptors, CXCR4; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D010768:Phosphoserine; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D016203:CDC2 Protein Kinase
keywords: Non-programmatic