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.
Huang
R P
RP
Burnham Institute, La Jolla Cancer Research Center, California 92037, USA.
Fan
Y
Y
Ni
Z
Z
Mercola
D
D
Adamson
E D
ED
D016475:3T3 Cells; D000818:Animals; D001665:Binding Sites / Q000235:genetics / Q000502:physiology; D001667:Binding, Competitive / Q000502:physiology; D016384:Consensus Sequence; D004268:DNA-Binding Proteins / Q000494:pharmacology / Q000502:physiology*; D051766:Early Growth Response Protein 1; D005796:Genes / Q000235:genetics / Q000502:physiology; D017874:Immediate-Early Proteins; D007633:Keratins / Q000235:genetics; D051379:Mice; D011401:Promoter Regions, Genetic / Q000502:physiology; D011485:Protein Binding; D016329:Sp1 Transcription Factor / Q000494:pharmacology / Q000502:physiology*; D014157:Transcription Factors / Q000494:pharmacology / Q000502:physiology*; D015533:Transcriptional Activation / Q000187:drug effects; D016335:Zinc Fingers / Q000187:drug effects / Q000502:physiology
D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D017874:Immediate-Early Proteins; D016329:Sp1 Transcription Factor; D014157:Transcription Factors; D007633:Keratins