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  • The EMBO Journal (2002) 21, 4070 - 4080
  • doi:10.1093/emboj/cdf391

Sequential involvement of Cdk1, mTOR and p53 in apoptosis induced by the HIV-1 envelope

Maria Castedo1, Thomas Roumier1, Julià Blanco2, Karine F. Ferri1, Jordi Barretina2, Lionel A. Tintignac1, Karine Andreau1, Jean-Luc Perfettini1, Alessandra Amendola3, Roberta Nardacci3, Philip Leduc4, Donald E. Ingber4, Sabine Druillennec5, Bernard Roques5, Serge A. Leibovitch1, Montserrat Vilella-Bach6, Jie Chen6, José A. Este2, Nazanine Modjtahedi1, Mauro Piacentini3,7 and Guido Kroemer1

  1. Centre National de la Recherche Scientifique, UMR1599, Institut Gustave Roussy, 39 rue Camille-Desmoulins, F-94805 Villejuif, France
  2. Institut de Recerca de la SIDA-Caixa, Laboratori de Retrovirologia, Hospital Universitari Germans Trias i Pujol, Universitat Autónoma de Barcelona, Ctra Canyet s/n, 08916 Badalona, Catalonia, Spain
  3. Istituto Nazionale Malattie Infettive 'L. Spallanzani', Rome 00149, Italy
  4. Department of Surgery and Pathology, Children's Hospital and Harvard Medical School, Enders 1007, 300 Longwood Avenue, Boston, MA 02115 USA
  5. Unité de Pharmacochimie Moléculaire et Structurale, INSERM U266–CNRS UMR860, Université René Descartes (Paris V), F-75005 Paris, France
  6. Department of Cell and Structural Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
  7. Department of Biology, University of Rome Tor Vergata, Rome 00133, Italy

Correspondence to:

Guido Kroemer, E-mail: kroemer@igr.fr

Received 19 February 2002; Accepted 3 June 2002; Revised 29 May 2002

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 (p53S15), p53-dependent upregulation of Bax and activation of the mitochondrial death pathway. p53S15 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, p53S15 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 p53S15 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.

  • Keywords:

    • cell death,
    • cyclin B,
    • mitochondria,
    • p53,
    • rapamycin