THE TRANSCRIPTION OF THE INTERCELLULAR-ADHESION MOLECULE-1 IS REGULATED BY ETS TRANSCRIPTION FACTORS

The Ets family of transcription factors comprises several members whic h are involved to regulate gene transcription. Although several consen sus binding sites for Ets proteins can be found in a wide series of pr omoter, only a limited number of them are indeed activated by these tr anscription factors, The human intercellular adhesion molecule-1 (ICAM -1) plays a crucial role in immune responses by enabling the binding o f effector cells to various target cell types. ICAM-1 is constitutivel y expressed at different levels in the absence of stimuli in different cell types, and its expression is upregulated by several proinflammat ory cytokines. We hale here examined the transcriptional regulation of human ICAM-1 expression by Ets proteins, and more particularly by ERM , a member of this family of transcription factors, Transient transfec tion assays revealed that Ets-2 and ERM significantly activate the tra nscription of ICAM-1 promoter, whereas the less-related Ets family mem ber, Spi-1/Pu.1, failed to do so, Transfection of a series of ICAM-1 p romoter deletion mutants together with ERM expression plasmids have sh own that an Ets responsive element is located within the first 176 bp upstream from the translational start site. Electrophoretic mobility s hift assays and DNase I footprinting analysis have enabled us to ident ify two Ets binding sites at positions -158 and -138 from the ATG, res pectively. Site directed mutagenesis of these elements has shown that the distal site is the major element required for the ERM-mediated act ivation of the ICAM-1 promoter, We can thus conclude that expression o f ICAM-1 can be regulated by Ets transcription factors.