CD95/Fas signaling in T lymphocytes induces the cell cycle control protein p21cip-1/WAF-1, which promotes apoptosis

J Immunol. 2000 Apr 15;164(8):4032-6. doi: 10.4049/jimmunol.164.8.4032.

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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3T3 Cells
  • Amino Acid Chloromethyl Ketones / pharmacology
  • Animals
  • Apoptosis / genetics
  • Apoptosis / immunology*
  • Caspase Inhibitors
  • Cells, Cultured
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / biosynthesis*
  • Cyclins / physiology
  • Cysteine Proteinase Inhibitors / pharmacology
  • Ligands
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Oligopeptides / pharmacology
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • T-Lymphocytes / immunology*
  • Transfection
  • Tumor Suppressor Protein p53 / physiology
  • Up-Regulation / drug effects
  • Up-Regulation / immunology
  • fas Receptor / genetics
  • fas Receptor / immunology
  • fas Receptor / metabolism
  • fas Receptor / physiology*

Substances

  • Amino Acid Chloromethyl Ketones
  • Caspase Inhibitors
  • Cdkn1a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Cysteine Proteinase Inhibitors
  • Ligands
  • Oligopeptides
  • Tumor Suppressor Protein p53
  • aspartyl-glutamyl-valyl-aspartal
  • benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
  • fas Receptor