Ligand-independent anti-oncogenic activity of the alpha subunit of the type I interferon receptor.
Two interferon (IFN) alpha-regulated genes, IRF1/ISGF2 and PKR/p68 kinase, may function as tumor suppressor genes suggesting that the IFN system may function as a tumor suppressor system. We report that the expression 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 growth arrest normally occurs, and (iii) the tumorigenicity in nude mice. Furthermore, expression of the alpha subunit in K-562 cells induced erythroid differentiation. While most cytokine receptors become activated after binding their corresponding ligands, the overexpression of the alpha subunit has a physiological effect in the absence of its natural ligand, type I IFNs, suggesting a novel function for this type I IFN receptor subunit. The anti-oncogenic effect of the alpha subunit is mediated by a pathway that does not involve two tumor suppressor genes induced by type I IFNs, the transcriptional regulator IFN response factor-1 and the RNA-dependent protein kinase, or the p135tyk2 tyrosine kinase that directly associates and phosphorylates the alpha subunit.
Colamonici
O R
OR
Department of Pathology, University of Tennessee, Memphis 38163.
Porterfield
B
B
Domanski
P
P
Handa
R K
RK
Flex
S
S
Samuel
C E
CE
Pine
R
R
Diaz
M O
MO
D000818:Animals; D002455:Cell Division; D004268:DNA-Binding Proteins / Q000502:physiology; D004920:Erythropoiesis; D016147:Genes, Tumor Suppressor; D066298:In Vitro Techniques; D050856:Interferon Regulatory Factor-1; D004915:Leukemia, Erythroblastic, Acute / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D010750:Phosphoproteins / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000502:physiology; D017471:Receptors, Interferon / Q000737:chemistry / Q000502:physiology*; D015398:Signal Transduction; D053634:TYK2 Kinase; D014407:Tumor Cells, Cultured; D019892:eIF-2 Kinase
D004268:DNA-Binding Proteins; D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; D010750:Phosphoproteins; D011506:Proteins; D017471:Receptors, Interferon; D011505:Protein-Tyrosine Kinases; D053634:TYK2 Kinase; C499356:Tyk2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase