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 language | English |
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Pages (from-to) | 13547-13553 |
Number of pages | 7 |
Journal | Journal of Biological Chemistry |
Volume | 276 |
Issue number | 17 |
DOIs | |
State | Published - 2001 |
Externally published | Yes |
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