TY - JOUR
T1 - Sequential involvement of Cdk1, mTOR and p53 in apoptosis induced by the HIV-1 envelope
AU - Castedo, Maria
AU - Roumier, Thomas
AU - Blanco, Julià
AU - Ferri, Karine F.
AU - Barretina, Jordi
AU - Tintignac, Lionel A.
AU - Andreau, Karine
AU - Perfettini, Jean Luc
AU - Amendola, Alessandra
AU - Nardacci, Roberta
AU - Leduc, Philip
AU - Ingber, Donald E.
AU - Druillennec, Sabine
AU - Roques, Bernard
AU - Leibovitch, Serge A.
AU - Vilella-Bach, Montserrat
AU - Chen, Jie
AU - Este, José A.
AU - Modjtahedi, Nazanine
AU - Piacentini, Mauro
AU - Kroemer, Guido
PY - 2002/8/1
Y1 - 2002/8/1
N2 - 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.
AB - 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.
KW - Cell death
KW - Cyclin B
KW - Mitochondria
KW - Rapamycin
KW - p53
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U2 - 10.1093/emboj/cdf391
DO - 10.1093/emboj/cdf391
M3 - Article
C2 - 12145207
AN - SCOPUS:18444416812
SN - 0261-4189
VL - 21
SP - 4070
EP - 4080
JO - EMBO Journal
JF - EMBO Journal
IS - 15
ER -