STAT4, A NOVEL GAMMA-INTERFERON ACTIVATION SITE-BINDING PROTEIN EXPRESSED IN EARLY MYELOID DIFFERENTIATION

Interferon regulation of gene expression is dependent on the tyrosine phosphorylation and activation of the DNA-binding activity of two rela ted proteins of 91 kDa (STAT1) and/or 113 kDa (STAT2). Recent studies have suggested that these proteins are substrates of Janus kinases and that proteins related to STAT1 are involved in a number of signalling pathways, including those activated in myeloid cells by erythropoieti n and interleukin-3 (IL-3). To clone STAT-related proteins from myeloi d cells, degenerate oligonucleotides were used in PCRs to identify nov el family members expressed in myeloid cells. This approach allowed th e identification and cloning of the Stat4 gene, which is 52% identical to STAT1. Unlike STAT1, Stat4 expression is restricted but includes m yeloid cells and spermatogonia. In the erythroid lineage, Stat4 expres sion is differentially regulated during differentiation. Functionally, Stat4 has the properties of other STAT family genes. In particular, c otransfection of expression constructs for Stat4 and Jak1 or Jak2 resu lts in the tyrosine phosphorylation of Stat4 and the acquisition of th e ability to bind to the gamma interferon (IFN-gamma)-activated sequen ce of the interferon regulatory factor 1 (IRF-1) gene. Stat4 is locate d on mouse chromosome 1 and is tightly linked to the Stat1 gene, sugge sting that the genes arose by gene duplication. Unlike Stat1, neither IFN-alpha nor IFN-gamma activates Stat4. Nor is Stat4 activated in mye loid cells by a number of cytokines, including erythropoietin, IL-3, g ranulocyte colony-stimulating factor, stem cell factor, colony-stimula ting factor 1, hepatocyte growth factor, IL-2, IL-4, and IL-6.