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Regulation of Interferon- (IFN-) Gene Promoters by Growth Factors that Target the Ets-2 Composite Enhancer: A Possible Model for Maternal Control of IFN- Production by the Conceptus during Early Pregnancy

Department of Animal Sciences, University of Missouri, Columbia, Missouri 65211

Address all correspondence and requests for reprints to: R. Michael Roberts, 158 Animal Sciences Research Center, University of Missouri-Columbia, 920 East Campus Drive, Columbia, Missouri 65211-5300. E-mail: robertsrm{at}missouri.edu.

Expression of interferon- 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- production.

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