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

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 e ects 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-mostransformed cells, nor was CDC2 or cyclin B1 downregulated in those cells. These ®ndings 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 vmos that overrides the G2/M arrest induced by PKR. Oncogene (2001) 20, 8045 ± 8056.

A Novel Anticancer Ribonucleoside, 1-(3-C-Ethynyl-β-D-ribo-pentofuranosyl)Cytosine, Enhances Radiation-Induced Cell Death in Tumor Cells

“…The inhibition of Chk1 by UCN-01 and SB-218078 and the inhibition of ATM and ATR by caffeine were proposed as mechanisms of the abrogation of the G 2 /M checkpoint. Moreover, the down-regulation of Cdc2 and cyclin B1 by overexpression of double-stranded RNA-activated, serine/threonine protein kinase, PKR, was shown to induce apoptosis in CHO cells (36). In the present experiments, we found that a low concentration of a novel antitumor agent, TAS106, enhanced radiation-induced apoptosis and reproductive cell death, as shown in Fig.…”

Thr 446 phosphorylation of PKR by HCV core protein deregulates G2/M phase in HCC cells

“…They also indicate the existence of an additional PKR-dependent pathway, which regulates HCV core-dependent G2/M arrest. PKR has been reported to slow down the S phase entry (Tan and Katze, 1999;Zamanian-Daryoush et al, 1999) and ectopic expression of PKR induces arrest in G2/M phase (Dagon et al, 2001). We highlight the important role of PKR in the control of mitosis in HCC core positive cell lines.…”

“…PKR may mediate G2/M phase accumulation interfering with cyclin B1 and cdk1 expression (Dagon et al, 2001). According to these data, we asked whether the HCV core-dependent G2/M accumulation could be related to the presence of PKR.…”

“…Recent evidences have implicated PKR in cell cycle regulation. A pivotal role for PKR in regulating the G2/ M phase has been described (Zamanian-Daryoush et al, 1999;Dagon et al, 2001), as an additional mechanism to p53-mediated control of G2/M phase progression (Taylor and Stark, 2001;Fulco et al, 2003). It is not surprising that HCV, as well as many other viruses, is able to block or evade the antiviral PKR activity.…”

PKR is activated by cellular dsRNAs during mitosis and acts as a mitotic regulator

“…PKR activity is modulated in proliferation and cell cycle progression, with its peak activity at the G1/S transition in T98G glioblastoma cells (Zamanian-Daryoush et al 1999). Long-term overexpression of PKR led to G2/M-phase arrest in CHO cells (Dagon et al 2001). Furthermore, PKR has been shown to act as a tumor suppressor, as overexpression of transdominant-negative PKR (TN PKR) induced malignant transformation in NIH 3T3 cells (Koromilas et al 1992).…”