Signal transduction pathways in the induction of 2',5'-oligoadenylate synthetase gene expression by interferon alpha/beta.

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Abstract
Treatment of quiescent BALB/c mouse 3T3 cells with murine interferon .alpha./.beta. (IFN-.alpha./.beta.) (1000 units/ml) leads to the appearance at 4 hr of 1.7-kilobase 2'',5''- oligoadenylate (2'',5''-OAS) mRNA as detected by Northern blot analysis. This mRNA accumulates for at least 18 hr. Two protein kinase C activators, 1,2-dioctanoyl glycerol and phorbol 12-myristate 13-acetate, suppress, whereas the calcium ionophore ionomycin enhances, the IFN-.alpha./.beta.-induced expression of 2'',5''-OAS mRNA. The 8-bromo and dibutyryl analogs of cAMP and the adenylate cyclase activator forskolin did not affect the induction of 2'',5''-OAS mRNA by IFN-.alpha./.beta.. In the absence of IFN-.alpha./.beta., the above agents used either singly or in combinations, did not induce 2'',5''-OAS mRNA expression nor did platelet-derived growth factor (1-2 units/ml), fibroblast growth factor (6-100 ng/ml), or bovine serum (10-20%). Bovine serum also did not affect 2'',5'',-OAS mRNA induction by IFN-.alpha./.beta.. The poly(ADP)-ribose synthetase inhibitor 3- aminobenzamide suppressed IFN-.alpha./.beta.-induced 2'',5''-OAS gene expression. These results suggest that in quiescent BALB/c 3T3 cells (i) the 2'',5''-OAS gene is not responsive to the three major signal transduction pathways activated by diaclygycerol, Ca2+, and cAMP; (ii) induction of the 2'',5''- OAS gene by IFN-.alpha./.beta. is decreased by activation of the protein kinase C pathway but enhanced by elevation of intracellular [Ca+2].