Abstract
Ligation of CD95 on T lymphocytes resulted in the up-regulation of a cell cycle control protein, p21cip-1/WAF-1, an inhibitor of cyclin-dependent kinases. This up-regulation was completely blocked by the cysteine protease inhibitor Z-VAD-fmk (benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone), whereas DEVD-CHO (succinyl-Asp-Glu-Val-Asp-aldehyde), a caspase 3 inhibitor, had no effect. In Faslpr-cg mice, a point mutation in the death domain of CD95 results in failure to recruit FADD (Fas-associated death domain), and in the present study this mutation prevented both CD95-mediated apoptosis and p21cip-1/WAF-1 induction. During apoptotic cell death due to irradiation, p21cip-1/WAF-1 is up-regulated by a p53-dependent pathway that responds to DNA damage. However, CD95-induced up-regulation of p21cip-1/WAF-1 in T cells was p53-independent. T cells deficient in p21cip-1/WAF-1 were less susceptible to CD95-induced apoptosis. We conclude that in T cells, ligation of CD95 and activation of caspases cause the induction of p21cip-1/WAF-1, which acts to promote cell death.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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3T3 Cells
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Amino Acid Chloromethyl Ketones / pharmacology
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Animals
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Apoptosis / genetics
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Apoptosis / immunology*
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Caspase Inhibitors
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Cells, Cultured
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins / biosynthesis*
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Cyclins / physiology
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Cysteine Proteinase Inhibitors / pharmacology
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Ligands
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Lymphocyte Activation / immunology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Oligopeptides / pharmacology
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Signal Transduction / genetics
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Signal Transduction / immunology*
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T-Lymphocytes / immunology*
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Transfection
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Tumor Suppressor Protein p53 / physiology
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Up-Regulation / drug effects
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Up-Regulation / immunology
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fas Receptor / genetics
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fas Receptor / immunology
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fas Receptor / metabolism
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fas Receptor / physiology*
Substances
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Amino Acid Chloromethyl Ketones
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Caspase Inhibitors
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Cdkn1a protein, mouse
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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Cysteine Proteinase Inhibitors
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Ligands
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Oligopeptides
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Tumor Suppressor Protein p53
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aspartyl-glutamyl-valyl-aspartal
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benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
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fas Receptor