Double-stranded RNA-dependent protein kinase, PKR, down-regulates CDC2/cyclin B1 and induces apoptosis in non-transformed but not in v-mos transformed cells

Yossi Dagon, Sara Dovrat, Shlomit Vilchik, Dalia Hacohen, Gilat Shlomo, Benjamin Sredni, Samuel Salzberg, Uri Nir

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

The interferon (IFN)-induced, double stranded RNA (dsRNA)-activated serine/threonine kinase, PKR, is a potent negative regulator of cell growth when overexpressed in yeast or mammalian cells. Paradoxically, while it can function as a tumor suppressor and inducer of apoptosis, it is overexpressed in a variety of human cancers. To resolve this enigma, we established cell-lines that overexpress PKR in non-transformed and in v-mos transformed CHO cells. Overexpression of PKR suppressed the proliferation of CHO cells by inducing a transient G0/G1 arrest, followed by a delayed G2/M arrest, which attenuated cell cycle progression. These effects were accompanied by early induction of p21/WAF-1 and delayed downregulation of CDC2 and cyclin B1. Induction of proapoptotic activity of the ectopic PKR paralleled the onset of G2/M arrest in CHO cells. However, while transiently inducing p21/WAF-1, PKR did not impose G2/M arrest or apoptosis in v-mos-transformed cells, nor was CDC2 or cyclin B1 down-regulated in those cells. These findings link the proapoptotic activity of PKR to the arrest of cell cycle at the G2/M phase. Consequently, the apoptotic activity of PKR could be counter-acted by an oncogene-like v-mos that overrides the G2/M arrest induced by PKR.

Original languageEnglish
Pages (from-to)8045-8056
Number of pages12
JournalOncogene
Volume20
Issue number56
DOIs
StatePublished - 6 Dec 2001

Bibliographical note

Funding Information:
We thank Uri Karo for his help with the flow-cytometry analysis and Avrille Goldreich for typing this manuscript. This work was supported by research grants from the Israel Cancer Research fund, the Israel Cancer Association (Melul Foundation, in memory of the late Prof N Trainin) and the CapCURE Research fund.

Keywords

  • CDC2
  • Cell cycle
  • PKR
  • V-mos

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