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

Maria Castedo, Thomas Roumier, Julià Blanco, Karine F. Ferri, Jordi Barretina, Lionel A. Tintignac, Karine Andreau, Jean Luc Perfettini, Alessandra Amendola, Roberta Nardacci, Philip Leduc, Donald E. Ingber, Sabine Druillennec, Bernard Roques, Serge A. Leibovitch, Montserrat Vilella-Bach, Jie Chen, José A. Este, Nazanine Modjtahedi, Mauro PiacentiniGuido Kroemer

Research output: Contribution to journalArticle

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 (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.

Original languageEnglish (US)
Pages (from-to)4070-4080
Number of pages11
JournalEMBO Journal
Volume21
Issue number15
DOIs
StatePublished - Aug 1 2002

Keywords

  • Cell death
  • Cyclin B
  • Mitochondria
  • Rapamycin
  • p53

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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  • Cite this

    Castedo, M., Roumier, T., Blanco, J., Ferri, K. F., Barretina, J., Tintignac, L. A., Andreau, K., Perfettini, J. L., Amendola, A., Nardacci, R., Leduc, P., Ingber, D. E., Druillennec, S., Roques, B., Leibovitch, S. A., Vilella-Bach, M., Chen, J., Este, J. A., Modjtahedi, N., ... Kroemer, G. (2002). Sequential involvement of Cdk1, mTOR and p53 in apoptosis induced by the HIV-1 envelope. EMBO Journal, 21(15), 4070-4080. https://doi.org/10.1093/emboj/cdf391