Abstract
In this study, we showed the existence of a positive correlation between the amount of human immunodeficiency virus-type 1 (HIV-1) RNA in HIV-1 seropositive subjects and the plasma levels of TRAIL. Since it has been previously demonstrated that HIV-1 Tat protein up-regulates the expression of TRAIL in monocytic cells whereas tat-expressing lymphoid cells are more resistant to TRAIL cytotoxicity, we next investigated the effect of Tat on the expression/activity of both apical caspase-8 and -10, which play a key role in mediating the initial phases of apoptosis by TRAIL, and c-FLIP. Jurkat lymphoblastoid human T cell lines stably transfected with a plasmid expressing wild-type (HIV-1) tat gene showed normal levels of caspase-8 but significantly decreased levels of caspase-10 at both mRNA and protein levels with respect to Jurkat transfected with the control plasmid or with a mutated (cys22) non-functional tat cDNA. A significant decrease of caspase-10 expression/activity was also observed in transient transfection experiments with plasmid carrying tat cDNA. Moreover, c-FLIP(L) and c-FLIP(S) isoforms were up-regulated in tat-expressing cells at both mRNA and protein level in comparison with control cells. Taken together, these results provide a molecular basis to explain the resistance of tat-expressing Jurkat cells to apoptosis induced by TRAIL and, possibly, to other death-inducing ligands.
Copyright 2004 Wiley-Liss, Inc.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antibody-Dependent Cell Cytotoxicity / genetics
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Apoptosis / genetics
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Apoptosis Regulatory Proteins
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CASP8 and FADD-Like Apoptosis Regulating Protein
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CD4-Positive T-Lymphocytes / drug effects
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CD4-Positive T-Lymphocytes / metabolism*
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Caspase 10
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Caspase 8
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Caspases / drug effects
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Caspases / genetics
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Caspases / metabolism*
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Cell Survival / genetics
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DNA, Complementary / genetics
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Down-Regulation / genetics
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Gene Products, tat / genetics
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Gene Products, tat / metabolism*
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Gene Products, tat / pharmacology
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HIV Infections / blood*
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HIV Infections / genetics
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HIV-1 / genetics
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HIV-1 / metabolism*
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Humans
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Intracellular Signaling Peptides and Proteins / drug effects
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Intracellular Signaling Peptides and Proteins / metabolism*
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Jurkat Cells
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Membrane Glycoproteins / blood*
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Membrane Glycoproteins / toxicity
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Mutation / genetics
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RNA, Messenger / metabolism
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RNA, Viral / genetics
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RNA, Viral / metabolism
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TNF-Related Apoptosis-Inducing Ligand
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Tumor Necrosis Factor-alpha / toxicity
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Up-Regulation / genetics
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tat Gene Products, Human Immunodeficiency Virus
Substances
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Apoptosis Regulatory Proteins
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CASP8 and FADD-Like Apoptosis Regulating Protein
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CFLAR protein, human
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DNA, Complementary
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Gene Products, tat
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Intracellular Signaling Peptides and Proteins
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Membrane Glycoproteins
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RNA, Messenger
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RNA, Viral
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TNF-Related Apoptosis-Inducing Ligand
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TNFSF10 protein, human
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Tumor Necrosis Factor-alpha
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tat Gene Products, Human Immunodeficiency Virus
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CASP8 protein, human
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Caspase 10
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Caspase 8
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Caspases
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CASP10 protein, human