LIGAND-INDEPENDENT ANTI-ONCOGENIC ACTIVITY OF THE ALPHA SUBUNIT OF THE TYPE-I INTERFERON RECEPTOR

Two interferon (IFN) alpha-regulated genes, 1RF1/ISGF2 and PKR/p68 kin ase, may function as tumor suppressor genes suggesting that the IFN sy stem may function as a tumor suppressor system. We report that the exp ression of the alpha subunit of the type I IFN receptor in human K-562 cells had anti-oncogenic effects that include a marked decrease in: ( i) cell proliferation rate, (ii) the cell density at which grow th arr est normally occurs, and (iii) the tumorigenicity in nude mice. Furthe rmore, expression of the alpha subunit in R-562 cells induced erythroi d differentiation. While most cytokine receptors become activated afte r binding their corresponding ligands, the overexpression of the alpha subunit has a physiological effect in the absence of its natural liga nd, type I IFNs, suggesting a novel function for this type I IFN recep tor subunit. The anti-oncogenic effect of the alpha subunit is mediate d by a pathway that does not involve two tumor suppressor genes induce d by type I IFNs, the transcriptional regulator IFN response factor-1 and the RNA-dependent protein kinase, or the p135(tyk2) tyrosine kinas e that directly associates and phosphorylates the or subunit.