Regulation of interferon-tau (IFN-tau) gene promoters by growth factors that target the Ets-2 composite enhancer: a possible model for maternal control of IFN-tau 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.
Ezashi
Toshihiko
T
Department of Animal Sciences, University of Missouri-Columbia, 920 East Campus Drive, Columbia, Missouri 65211-5300, USA.
Roberts
R Michael
RM
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000502:physiology; D002417:Cattle; D004742:Enhancer Elements, Genetic / Q000502:physiology*; D005260:Female; D005333:Fetus / Q000378:metabolism*; D017930:Genes, Reporter / Q000502:physiology; D006133:Growth Substances / Q000502:physiology*; D007370:Interferon Type I / Q000096:biosynthesis / Q000235:genetics*; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D051379:Mice; D008954:Models, Biological; D010766:Phosphorylation; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000096:biosynthesis / Q000235:genetics*; D011270:Pregnancy, Animal / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000502:physiology*; D017434:Protein Structure, Tertiary / Q000502:physiology; D050787:Proto-Oncogene Protein c-ets-2; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D018631:ras Proteins / Q000502:physiology
C494070:Ets2 protein, mouse; D006133:Growth Substances; D007370:Interferon Type I; D011257:Pregnancy Proteins; D050787:Proto-Oncogene Protein c-ets-2; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D015534:Trans-Activators; D018808:Transcription Factor AP-1; C020947:interferon tau; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor; D018631:ras Proteins