MOLECULAR MECHANISMS OF INTERFERON-BETA GENE INDUCTION

The Type 1 interferon genes (IFNA and IFNB) have served as an important paradigm to examine the mechanisms of virus inducible gene expression. In particular IFNB has been amenable to reverse genetic approaches for the analysis of transcriptional activation. The DNA sequences that regulate IFNB gene transcription are located within a 110 nucleotide region, immediately upstream of the structural gene and consist of multiple, overlapping positive and negative regulatory domains essential for virus-induced activation and/or repression of the promoter The positive regulatory domains I and III (PRDI and PRDIII) interact with several proteins, including interferon regulatory factors IRF-1 and IRF-2, while the PRDII domain interacts with subunits of the NF-kappa B/Rel family of transcription factors. PRDIV interacts with ATF-2 and c-jun. An 11bp element (-60 to -50) acts as a negative regulatory element (NRE) of the PRDII domain and binds a HMG-like protein that can interact specifically with the p50 subunit of NF-kappa B. In-vivo synergism between PRDIV and PRDII is provide by the binding- of the high mobility group I/Y proteins to the minor groove of DNA within AT rich sites in PRDIV and PRDII; HMG I/Y proteins appear to facilitate the binding of NF-kappa B and ATF-2 by bending DNA.