Alpha/beta and gamma type interferons (IFN), act through distinct cell surface receptors and induce transcription of an overlapping sets of genes. MHC class I genes are inducible by both type of interferons. We have analyzed a gastric tumor cell line, AGS, which was completely defective in MHC class I response to interferon-alpha and gamma. Northern blot analysis demonstrated that the lack of IFN response was related with the absence of up-regulation of specific HLA class I mRNA. Electrophoretic mobility shift assays in various tumor cell lines after IFN-alpha and IFN-gamma treatment showed differential binding of the transcriptional factors to MHC class I regulatory elements. Comparison of kappa-B binding activity showed that IFN-alpha and IFN-gamma induced opposite changes in NF-kappa B binding activity in AGS cells, indicating that the absence of MHC class I response in AGS appears to be independent of kappa-B activity. In contrast, there were remarkable differences in the level of transcriptional factor binding to an interferon-responsive sequence element (IRSE), between AGS and other interferon-responsive tumor cell lines. This result suggests that the low level of transcriptional factor binding to IRSE in AGS cells was responsible of the lack of induction of MHC class I antigens. In this context, overlapping factors in the signal transduction pathway of both type I and II interferons may be involved in the non-responsiveness of this gastric carcinoma tumor cell line.