Genetic analyses of mutants have yielded valuable information about p91-associated interferon signal transduction. It was thus discovered that p91 is an essential protein for the induction of both type I and type II interferons. We previously reported the development of ME180 mutants resistant to interferon-gamma because of a signaling defect resulting in the loss of IDO induction. IDO does not respond to type I interferon despite an ISRE-like sequence upstream of the coding region. However, the IDO mutants were found to be cross-resistant to the growth-inhibitory effects of type I interferon. We therefore examined the effects of both types of interferon on interferon-stimulated gene mRNA accumulation and examined alterations in cellular protein introduced by the mutation. The induction of the p91-responsive gene 6-16 was not altered in either of the mutants, and the early-induced gene IRF1 exhibited differences only in the kinetics of mRNA accumulation. The later induced gene, p68, also exhibited different kinetics, possibly reflecting the changes in IRF1. Immunoprecipitated p91 exhibited normal, interferon-induced phosphorylation in both mutants. Two-dimensional gel electrophoresis revealed that the mutant cells contained 20 peptides with altered biochemistry. These results suggest that IDO induction is controlled by a distinct set of proteins not directly correlated with p91 activation.