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Castedo, M. et al.

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

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.[1]

References

Sequential involvement of Cdk1, mTOR and p53 in apoptosis induced by the HIV-1 envelope. 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., Piacentini, M., Kroemer, G. EMBO J. (2002) [Pubmed]

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