Vanadate Facilitates Interferon α-mediated Apoptosis That Is Dependent on the Jak/Stat Pathway

Ana M. Gamero, Andrew C. Larner

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

Type I Interferon (IFN)-dependent inhibition of cell growth can occur either in the absence or presence of apoptosis. The mechanisms that determine whether or not cells undergo apoptosis after exposure to IFN-α are not clear. This study shows that a variety of cell lines that display growth inhibition but not apoptosis in response to IFN-α will undergo programmed cell death when low concentrations of the protein-tyrosine phosphatase inhibitor vanadate are added with IFN-α. In contrast, the combination of tumor necrosis factor-α with vanadate did not trigger apoptosis in these cells. Caspase-3 activity was detected only in cells exposed to IFN-α and vanadate but not to IFN-α or vanadate alone. The ability of IFN-α and vanadate to induce apoptosis did not require expression of p53 and was blocked by N-acetyl-L-cysteine. Activation of the Jak/Stat pathway and expression of IFN-inducible genes was not altered by incubation of cells with IFN-α and vanadate compared with IFN-α alone. However, mutant cells lacking Stat1, Stat2, Jak1, or Tyk2, or cells expressing kinase inactive Jak1 or Tyk2 did not undergo apoptosis in the presence of IFN-α and vanadate. These results suggest that IFN-α stimulation of Stat-dependent genes is necessary, but not sufficient, for this cytokine to induce apoptosis. Another signaling cascade that involves the activity of a protein-tyrosine phosphatase and/or the generation of reactive oxygen species may play an important role in promoting IFN-α-induced apoptosis.

Original languageEnglish
Pages (from-to)13547-13553
Number of pages7
JournalJournal of Biological Chemistry
Volume276
Issue number17
DOIs
StatePublished - 2001
Externally publishedYes

Keywords

  • Acetylcysteine/metabolism
  • Apoptosis/drug effects
  • Caspase 3
  • Caspases/metabolism
  • Cell Line
  • DNA-Binding Proteins/metabolism
  • Dose-Response Relationship, Drug
  • Enzyme Activation
  • Enzyme Inhibitors/pharmacology
  • HeLa Cells
  • Humans
  • Immunoblotting
  • Interferon-alpha/metabolism
  • Janus Kinase 1
  • Jurkat Cells
  • Mutation
  • Phosphorylation
  • Protein-Tyrosine Kinases/metabolism
  • Proteins/metabolism
  • Reactive Oxygen Species/metabolism
  • Ribonucleases/metabolism
  • STAT1 Transcription Factor
  • STAT2 Transcription Factor
  • Signal Transduction
  • TYK2 Kinase
  • Time Factors
  • Trans-Activators/metabolism
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha/metabolism
  • Tumor Suppressor Protein p53/metabolism
  • Tyrosine/metabolism
  • Vanadates/metabolism

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