Regulation of interferon-γ (IFN-γ) gene promoters by growth factors that target the Ets-2 composite enhancer:: A possible model for maternal control of IFN-τ production by the conceptus during early pregnancy

Expression of interferon-tau gene (IFNT) by conceptuses of cattle and sheep must be in phase with the physiological state of the mother if the pregnancy is to be successful. IFNT has a close-to-consensus AP1 site ( - 71 to - 64), overlapping a binding site for Ets-2 ( - 79 to - 70), the key transcription factor controlling IFNT expression. When a bovine IFNT gene control region-luciferase (luc) construct was transfected into mouse 3T3 fibroblasts in the presence of Ets-2 and oncogenic Ras, luc expression was activated (50- to 100-fold). Mutations in either the activator protein 1 (AP1) site or the Ets-2 site of this construct abolished this effect. Similarly, a mutation of Thr72 of the Ets-2 or the addition of a specific inhibitor for the MAPK signal transduction pathway also markedly reduced expression. IFNT promoter activity was up-regulated in response to colony-stimulating factor-1 in 3T3 cells expressing the colony-stimulating factor-1 receptor c-fms. This response did not occur when the AP1 site or the Ets-2 binding sites were mutated. Nor was the response observed in 3T3 cells expressing an inactive form of c-fms. The experiments indicate that IFNT can be activated by growth factors operating through the Ras/MAPK pathway. The Ets-2 and AP1 binding sites are essential for such effects. The AP1 site, however, is noncanonical and unable to bind either cJun or cFos. These data emphasize the importance of a complex Ets-2 enhancer for expression of IFNT and suggest a means whereby the mother can exert control over conceptus IFN-tau production.