Reciprocal modulation between Sp1 and Egr‐1

Many ubiquitously expressed genes, including oncogenes, lack a proximal TATA or CAAT box but have a region of G + C‐rich sequences that appears to replace the usual promoter initiation site. The zinc‐finger protein Sp1 is one of the prevalent activators of these genes. The Egr‐1 zinc‐finger protein has a similar binding site and if the two sites occur in the same region, a variety of activation or inhibitory responses may be obtained. We show that competition between the two factors for overlapping sites on growth‐promoting genes could explain why the overexpression of Egr‐1 suppresses transformed growth in a number of cell types [Huang et al. (1995): Cancer Res 55:5054–5062; Huang et al. (1997): Int J Cancer]. We demonstrate here that Egr‐1 and Sp1 can bind to the same G + C‐rich sites and that Egr‐1 can displace Sp1 and hence inhibit its activity. We measured the responses of synthetic consensus binding sites and natural promoter sequences linked to a reporter gene and showed that Egr‐1 inhibited the activation of transcription by Sp1 on overlapping Sp1/Egr‐1 sites. In contrast, Sp1 activity could be augmented by Egr‐1 at nonoverlapping sites in the Egr‐1 gene promoter, in transient reporter gene studies in Drosophila SL2 cells. In addition, over‐expression of exogenous Sp1 in mammalian cells, also leads to increased Egr‐1 protein expression, which further inhibits Sp1 transactivation of numerous genes. Therefore, we can account for some of the complex responses of G + C‐rich enhancer/promoters by a form of “facilitated inhibition” of Sp1 by Egr‐1 at overlapping sites. J. Cell. Biochem. 66:489–499, 1997. © 1997 Wiley‐Liss, Inc.