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 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.
Dagon
Y
Y
Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel.
Dovrat
S
S
Vilchik
S
S
Hacohen
D
D
Shlomo
G
G
Sredni
B
B
Salzberg
S
S
Nir
U
U
D000818:Animals; D017209:Apoptosis; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D016466:CHO Cells; D002453:Cell Cycle; D002455:Cell Division; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D006224:Cricetinae; D019926:Cyclin B / Q000378:metabolism*; D056744:Cyclin B1; D015536:Down-Regulation; D004441:Ecdysterone / Q000031:analogs & derivatives* / Q000494:pharmacology; D005434:Flow Cytometry; D007700:Kinetics; D017232:Oncogene Proteins v-mos / Q000235:genetics / Q000494:pharmacology*; D014162:Transfection; D014170:Transformation, Genetic; D019892:eIF-2 Kinase / Q000235:genetics / Q000502:physiology*
C534699:CCNB1 protein, human; D019926:Cyclin B; D056744:Cyclin B1; D017232:Oncogene Proteins v-mos; C055348:muristerone A; D004441:Ecdysterone; D019892:eIF-2 Kinase; D016203:CDC2 Protein Kinase