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

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 8208664 Publication Model: Print Cited Medium: Print ISSN: 0261-4189 (Print) Linking ISSN: 02614189 NLM ISO Abbreviation: EMBO J Subsets: MEDLINE

Publication: 2024- : [London] : Nature Publishing Group
Original Publication: Eynsham, Oxford, England : Published for the European Molecular Biology Organization by IRL Press, [c1982-

Proto-Oncogene Proteins c-bcl-2*; Apoptosis/*physiology ; CD4 Antigens/*physiology ; CDC2 Protein Kinase/*physiology ; Cell Nucleus/*physiology ; Gene Products, env/*physiology ; HIV-1/*physiology ; Protein Kinases/*physiology ; Signal Transduction/*physiology ; Tumor Suppressor Protein p53/*physiology; Adult ; Antiretroviral Therapy, Highly Active ; CD4 Antigens/genetics ; CD4-Positive T-Lymphocytes/enzymology ; CD4-Positive T-Lymphocytes/pathology ; CD4-Positive T-Lymphocytes/virology ; CDC2 Protein Kinase/antagonists & inhibitors ; Cell Cycle Proteins/biosynthesis ; Cell Cycle Proteins/genetics ; Cell Nucleus/ultrastructure ; Gene Expression Profiling ; Giant Cells/cytology ; HIV Infections/blood ; HIV Infections/drug therapy ; HIV Infections/immunology ; HeLa Cells/cytology ; Humans ; Leukocytes, Mononuclear/metabolism ; Leukocytes, Mononuclear/virology ; Macromolecular Substances ; Membrane Fusion ; Mitochondria/physiology ; Neoplasm Proteins/physiology ; Nuclear Envelope/physiology ; Nuclear Envelope/ultrastructure ; Phosphorylation ; Phosphoserine/chemistry ; Protein Processing, Post-Translational ; Proto-Oncogene Proteins/metabolism ; Receptors, CXCR4/genetics ; Receptors, CXCR4/physiology ; Recombinant Fusion Proteins/physiology ; TOR Serine-Threonine Kinases ; Tumor Suppressor Protein p53/antagonists & inhibitors ; Viral Load ; bcl-2-Associated X Protein

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.

Curr Opin Hematol. 2000 Jan;7(1):40-7. (PMID: 10608503)
Cell Death Differ. 2000 Nov;7(11):1137-9. (PMID: 11288697)
Proc Natl Acad Sci U S A. 2000 Feb 1;97(3):1178-83. (PMID: 10655504)
Proc Natl Acad Sci U S A. 2000 Feb 1;97(3):1269-74. (PMID: 10655520)
Cell Death Differ. 2001 Feb;8(2):127-36. (PMID: 11313714)
Cell Mol Life Sci. 2001 Apr;58(4):571-9. (PMID: 11361092)
Biochim Biophys Acta. 2001 May 28;1519(1-2):1-12. (PMID: 11406266)
J Virol. 2001 Aug;75(16):7266-79. (PMID: 11461999)
J Virol. 2001 Aug;75(16):7637-50. (PMID: 11462036)
Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11187-92. (PMID: 11572974)
J Exp Med. 2001 Oct 15;194(8):1097-110. (PMID: 11602639)
J Exp Med. 2001 Nov 5;194(9):1277-87. (PMID: 11696593)
Nat Cell Biol. 2001 Nov;3(11):1014-9. (PMID: 11715023)
Science. 2001 Nov 30;294(5548):1942-5. (PMID: 11729323)
J Virol. 2002 Jan;76(1):416-20. (PMID: 11739707)
J Biol Chem. 2002 Jan 11;277(2):1477-87. (PMID: 11689551)
Science. 1986 May 30;232(4754):1123-7. (PMID: 3010463)
Nature. 1986 Jul 31-Aug 6;322(6078):470-4. (PMID: 3016552)
Cell. 1990 May 18;61(4):591-602. (PMID: 2188731)
Cell. 1991 Mar 8;64(5):903-14. (PMID: 1825803)
Science. 1993 Dec 24;262(5142):2050-4. (PMID: 8266103)
EMBO J. 1994 Aug 15;13(16):3772-81. (PMID: 8070405)
Proc Natl Acad Sci U S A. 1995 Dec 5;92(25):11889-93. (PMID: 8524869)
Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):10775-8. (PMID: 8855256)
Science. 1997 May 30;276(5317):1425-8. (PMID: 9162012)
Biochemistry. 1998 May 5;37(18):6410-8. (PMID: 9572858)
Proc Natl Acad Sci U S A. 1998 Oct 13;95(21):12556-61. (PMID: 9770524)
Nature. 1999 Jan 14;397(6715):104-5. (PMID: 9923668)
Placenta. 1999 Jul-Aug;20(5-6):401-6. (PMID: 10419805)
Science. 1999 Sep 10;285(5434):1733-7. (PMID: 10481009)
Ann N Y Acad Sci. 1999;887:199-212. (PMID: 10668476)
Cancer Res. 2000 Mar 15;60(6):1492-7. (PMID: 10749110)
AIDS. 2000 Jun 16;14(9):1155-61. (PMID: 10894279)
Curr Biol. 2000 Jul 13;10(14):861-4. (PMID: 10899009)
J Exp Med. 2000 Oct 16;192(8):1081-92. (PMID: 11034598)
Blood. 2000 Nov 1;96(9):2951-64. (PMID: 11049971)
Genes Dev. 2000 Nov 1;14(21):2712-24. (PMID: 11069888)
Exp Cell Res. 2000 Nov 25;261(1):119-26. (PMID: 11082282)
Proc Natl Acad Sci U S A. 2000 Dec 19;97(26):14340-5. (PMID: 11114166)
J Cell Biochem. 2001;80(3):339-45. (PMID: 11135363)
FASEB J. 2001 Jan;15(1):5-6. (PMID: 11099484)
J Clin Invest. 2001 Jan;107(2):207-15. (PMID: 11160137)
J Exp Med. 2001 Feb 19;193(4):509-19. (PMID: 11181702)
Blood. 2001 Mar 15;97(6):1756-64. (PMID: 11238118)
FASEB J. 2001 Mar;15(3):758-67. (PMID: 11259394)
Virology. 2001 Mar 30;282(1):48-55. (PMID: 11259189)
J Exp Med. 2000 Jan 3;191(1):33-46. (PMID: 10620603)

Keywords: Non-programmatic

0 (BAX protein, human)
0 (CD4 Antigens)
0 (Cell Cycle Proteins)
0 (Gene Products, env)
0 (Macromolecular Substances)
0 (Neoplasm Proteins)
0 (Proto-Oncogene Proteins)
0 (Proto-Oncogene Proteins c-bcl-2)
0 (Receptors, CXCR4)
0 (Recombinant Fusion Proteins)
0 (Tumor Suppressor Protein p53)
0 (bcl-2-Associated X Protein)
17885-08-4 (Phosphoserine)
EC 2.7.- (Protein Kinases)
EC 2.7.1.1 (MTOR protein, human)
EC 2.7.11.1 (TOR Serine-Threonine Kinases)
EC 2.7.11.22 (CDC2 Protein Kinase)

Date Created: 20020730 Date Completed: 20020916 Latest Revision: 20211203

20250114

PMC126138

10.1093/emboj/cdf391

12145207