Role for the double-stranded RNA activated protein kinase PKR in E2F-1-induced apoptosis

Stephan A. Vorburger, Abujiang Pataer, Kazumi Yoshida, Glen N. Barber, Weiya Xia, Paul Chiao, Lee M. Ellis, Mien Chie Hung, Stephen G. Swisher, Kelly K. Hunt

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

The transcription factor E2F-1 induces cell cycle progression at the G1/S checkpoint, and deregulation of E2F-1 provokes apoptosis in a wide variety of malignant cells. To date only p14ARF and p73, a p53 homologue, have been identified as E2F-1-inducible genes capable of mediating an apoptotic response. Here we show that adenovirus-mediated E2F-1 overexpression in cancer cells induces expression and autophosphorylation of the double-stranded RNA-dependent protein kinase PKR leading to phosphorylation of its downstream target, the α-subunit of the eukaryotic translation initiation factor 2 (eIF-2α) and to apoptotic cell death. This PKR-dependent apoptosis occurs in cell lines with mutated p53 and in cell lines with mutated p53 and p73, and is significantly reduced by the chemical inhibition of PKR activation. Further, PKR-/- mouse embryo fibroblasts, but not PKR+/+ mouse embryo fibroblasts, demonstrate significant resistance to E2F-1-induced apoptosis. We conclude that an important pathway of E2F-1-mediated apoptosis is dependent on PKR activation and does not require p53 or p73.

Original languageEnglish (US)
Pages (from-to)6278-6288
Number of pages11
JournalOncogene
Volume21
Issue number41
DOIs
StatePublished - Jan 1 2002

Keywords

  • Adenovirus
  • E2F-1
  • Gene therapy
  • PKR, apoptosis

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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  • Cite this

    Vorburger, S. A., Pataer, A., Yoshida, K., Barber, G. N., Xia, W., Chiao, P., Ellis, L. M., Hung, M. C., Swisher, S. G., & Hunt, K. K. (2002). Role for the double-stranded RNA activated protein kinase PKR in E2F-1-induced apoptosis. Oncogene, 21(41), 6278-6288. https://doi.org/10.1038/sj.onc.1205761