INDUCTION OF EXPRESSION OF INTERFERON-STIMULATED GENE FACTOR-III (ISGF-3) PROTEINS BY INTERFERONS

Interferon-stimulated gene factor-3 (ISGF-3) is a multiprotein (113, 9 1, 84, and 48 kDa) transcriptional factor which regulates the expressi on of a specific set of genes, the interferon (IFN)-stimulated genes. In the studies presented here, we investigated the induction of synthe sis of proteins of the ISGF-3 complex by IFNs. We report that both IFN -alpha and IFN-gamma induce a 3- to 5-fold increased expression of p98 , p84, and p113 and their phosphotyrosine contents in a dose- and time -dependent manner. The IFN-mediated induction in the levels of p91 cor related well with the increased expression of steady-state levels of p 91 mRNA by IFNs. Increased levels of p91 and p84 became detectable aft er 6 and 4 h treatment with IFN-alpha and IFN-gamma, respectively, and reached a maximum 5.2-fold at 18 h by IFN-alpha and 4-fold at 15 h by IFN-gamma. The levels of p113 were induced up to 3-fold at 15 h by IF N-alpha or IFN-gamma. The induction of ISGF-3 proteins by IFNs was acc ompanied by an increase in the accumulation of p91, p84, and p113 in t he nucleus. The observed induction of increased expression of ISGF-3 p roteins does not require continuous presence of IFNs, as removal of IF Ns after 6 h of minimal treatment still resulted in a significant incr ease (2- to 4-fold) in the levels of expression of p91, p84, and p113 over an additional period of 12 h in culture, and induced proteins rem ained phosphorylated on tyrosine. The IFN-mediated increase in the syn thesis of ISGF-3 proteins was blocked by Actinomycin D. Extension of t hese investigations to other human and mouse responsive cells, Daudi, Hela, and NIH3T3, also demonstrated significant increase in the levels of p91, p84, and p113 by interferons. (C) 1995 Academic Press, Inc.