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We have carried out experiments to determine which members of the rel family of transcription factors are involved in virus induction of the beta interferon (IFN-beta) gene. First, we examined the inducibility of artificial DNA binding sites that preferentially interact with different homo- or heterodimeric combinations of rel proteins in vitro. We found that only those sites capable of binding the p50/p65 heterodimer are virus inducible. Second, we analyzed a series of mutant rel DNA-binding sites in the context of the intact IFN-beta promoter. We found a correlation between (i) sites capable of binding both the p50/p65 heterodimer and the high-mobility-group protein HMG I(Y) and (ii) virus inducibility. Third, cotransfection of the IFN-beta gene enhancer/promoter with plasmids capable of expressing several different rel proteins revealed that only the combination of p50 and p65 efficiently activated transcription. Finally, we have used antibodies directed against different rel proteins to show that virus-inducible protein-DNA complexes assembled on the IFN-beta enhancer in vitro contain both p50 and p65. We conclude that the p50/p65 heterodimer is responsible for the NF-kappa B-dependent activation of the IFN-beta gene promoter in response to virus infection.