DOUBLE-STRANDED RNA-DEPENDENT PROTEIN-KINASE MEDIATES C-MYC SUPPRESSION INDUCED BY TYPE-I INTERFERONS

The antiproliferative functions of interferons result from specific ef fects that these cytokines exert on several cell cycle-controlling gen es. The possible coupling between the interferon-responsive genes that are directly transactivated by the interferon signaling and the genes that constitute the basic machinery of the cell cycle is not clear ye t, We report in this work that interferon-induced double-stranded RNA- activated kinase (PKR) is one of the specific mediators of the antipro liferative effects of the cytokine. Transfections of M1 myeloid leukem ia cells with two catalytically inactive mutant forms of PKR abrogated the ability of interferon to suppress c-Myc without interfering with the pRB/cyclin D responses. As a consequence, these genetically manipu lated cells displayed a small but significant reduction in their growt h sensitivity to interferons, a phenotype that characterizes a single pathway disruption. Transfection of the parental M1 cells with the fun ctional wildtype human PKR restricted their proliferation in the absen ce of interferons. This PKR-mediated growth inhibition could be effici ently rescued by the ectopic expression of deregulated c-myc. Taken to gether these results prove the existence of direct or indirect links b etween PKR and c-Myc suppression, thereby placing this gene along one of the complementary growth suppressive pathways that are triggered by interferons.