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

• Published in: The EMBO journal 2002-08, Vol.21 (15), p.4070-4080
• Main Authors: Castedo, Maria, Roumier, Thomas, Blanco, Julià, Ferri, Karine F., Barretina, Jordi, Tintignac, Lionel A., Andreau, Karine, Perfettini, Jean-Luc, Amendola, Alessandra, Nardacci, Roberta, Leduc, Philip, Ingber, Donald E., Druillennec, Sabine, Roques, Bernard, Leibovitch, Serge A., Vilella-Bach, Montserrat, Chen, Jie, Este, José A., Modjtahedi, Nazanine, Piacentini, Mauro, Kroemer, Guido
• Format: Article
• Language: English
• Subjects: Adult; Antiretroviral Therapy, Highly Active; Apoptosis - physiology; bcl-2-Associated X Protein; CD4 Antigens - genetics; CD4 Antigens - physiology; CD4-Positive T-Lymphocytes - enzymology; CD4-Positive T-Lymphocytes - pathology; CD4-Positive T-Lymphocytes - virology; CDC2 Protein Kinase - antagonists & inhibitors; CDC2 Protein Kinase - physiology; Cell Cycle Proteins - biosynthesis; Cell Cycle Proteins - genetics; cell death; Cell Nucleus - physiology; Cell Nucleus - ultrastructure; cyclin B; EMBO07; EMBO37; Gene Expression Profiling; Gene Products, env - physiology; Giant Cells - cytology; HeLa Cells - cytology; HIV Infections - blood; HIV Infections - drug therapy; HIV Infections - immunology; HIV-1 - physiology; Humans; Leukocytes, Mononuclear - metabolism; Leukocytes, Mononuclear - virology; Life Sciences; Macromolecular Substances; Membrane Fusion; mitochondria; Mitochondria - physiology; Neoplasm Proteins - physiology; Neutralization; Nuclear Envelope - physiology; Nuclear Envelope - ultrastructure; p53; Phosphorylation; Phosphoserine - chemistry; Protein Kinases - physiology; Protein Processing, Post-Translational; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-bcl-2; rapamycin; Receptors, CXCR4 - genetics; Receptors, CXCR4 - physiology; Recombinant Fusion Proteins - physiology; Signal Transduction - physiology; Space life sciences; TOR Serine-Threonine Kinases; Translocation; Tumor Suppressor Protein p53 - antagonists & inhibitors; Tumor Suppressor Protein p53 - physiology; Viral Load
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.1093/emboj/cdf391

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.