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

The interferon (IFN)-induced, double stranded RNA (dsRNA)-activated serine/ threonine kinase, PKR, is a potent negative regulator of cell growth when o verexpressed in yeast or mammalian cells. Paradoxically, while it can funct ion as a tumor suppressor and inducer of apoptosis, it is overexpressed in a variety of human cancers. To resolve this enigma, we established cell-lin es that overexpress PKR in non-transformed and in v-mos transformed CHO cel ls. Overexpression of PKR suppressed the proliferation of CHO cells by indu cing a transient G0/G1 arrest, followed by a delayed G2/M arrest, which att enuated cell cycle progression. These effects were accompanied by early ind uction of p21/ WAF-1 and delayed downregulation of CDC2 and cyclin B1. Indu ction of proapoptotic activity of the ectopic PKR paralleled the onset of G 2/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 wa s CDC2 or cyclin B1 downregulated in those cells. These findings link the p roapoptotic 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 on cogene-like v-mos that overrides the G2/M arrest induced by PKR.