EGR-1, THE RELUCTANT SUPPRESSION FACTOR - EGR-1 IS KNOWN TO FUNCTION IN THE REGULATION OF GROWTH, DIFFERENTIATION, AND ALSO HAS SIGNIFICANTTUMOR-SUPPRESSOR ACTIVITY AND A MECHANISM INVOLVING THE INDUCTION OF TGF-BETA-1 IS POSTULATED TO ACCOUNT FOR THIS SUPPRESSOR ACTIVITY

The transcription factor EGR-1 is a potential regulator of over 30 gen es and plays a role in growth, development, and differentiation and, i n addition, has significant transformation suppression activity. The r egulatory properties are reviewed and a hypothesis for the transformat ion suppression activity is proposed. EGR-1 contains three ''zinc-fing er'' motifs in the C-terminal portion of the molecule that constitute the DNA-binding domain and interact with the promoters by virtue of tw o classes of GC-rich elements: single GC-elements (GCEs) with the cons ensus 5'-T-G-C-G-T/g-G/A-G-G-C/a/t-G-G/T-3' and overlapping sites cons isting of an Sp-l binding site and the GCE consensus or close homolog of these sequences. The Wilm's tumor suppressor gene product WT1 inter acts with the same GCE and, owing in part to four alternate splice pro ducts, interacts with a broader range of GC-rich elements with the con sensus 5'-GNGNGGGNG-3' and 5'-TCCTCCTCCTCCTC-3'. WT1 commonly but not invariably acts as repressor of transcription, whereas EGR-1, in the a bsence of overlapping Sp-1 binding sequences, is often an activator. T he well-known rapid response of the EGR-1 gene following mitogenic sti mulation together with the occurrence of GCEs in the promoters of many growth factors and protooncogenes suggests a role of EGR-1 in growth. Moreover, EGR-1 is constitutively expressed in several viral-transfor med systems. On the other hand, studies of model and human tumor lines reveal that EGR-1 has significant growth and transformation suppressi on roles. Recent studies show that this effect can be accounted for by the ability of EGR-1 to induce the expression and secretion of TGF-Be ta 1, a potent growth suppressor of many cell types, by binding to a s ingle GCE of the TGF-Beta 1 promoter. Although the effects of EGR-1 at overlapping Sp1/EGR-1 DNA binding sites are not predictable, known ca ses fall into two loose groups. Sp1 is usually activating and increasi ng concentrations of EGR-1 lead to displacement that results in either inhibition of transactivation or EGR-1-dependent transactivation. Mor eover, recent studies suggest that displaced Sp1 binds to and activate s the endogenous Egr-1 gene, thereby leading to ''facilitated inhibiti on'' of Sp1 function by the resulting increased EGR-1. This effect may augment the growth suppressive function of EGR-1 based on induction o f TGF-Beta 1.