EGR-1 enhances tumor growth and modulates the effect of the Wilms' tumor 1gene products on tumorigenicity

The Wilms' tumor 1 gene (WT1) encodes a transcription factor of the zinc-fi nger family and is homozygously mutated or deleted in a subset of Wilms' tu mors. Through alternative mRNA splicing, the gene is expressed as four main polypeptides that differ by a stretch of 17 amino acids just N-terminal of the four zinc-fingers and three amino acids between zinc fingers 3 and 4, We have previously shown that expression of the WT1(-/-) isoform, lacking b oth inserts, increases the tumor growth rate of the adenovirus-transformed baby rat kidney (AdBRK) cell line 7C3H2, whereas expression of the WT1(-/+) isoform, lacking the 17aa insert, strongly suppresses the tumorigenic phen otype. In the present study we show that expression of these splice variant s does not affect the tumorigenic potential of the similar AdBRK cell line, 7C1T1, In contrast to the 7C3H2 cell line, this AdBRK cell line expresses high endogenous levels of EGR-1 (early growth response-1) protein, a transc ription factor structurally related to WT1, Ectopic expression of EGR-1 in the 7C3H2 AdBRK cells significantly increases their in vivo growth rate and nullifies the tumor suppressor activity of the WT1(-/+) protein. Furthermo re, we find that EGR-1 levels are elevated in some Wilms' tumors. These dat a are the first to show that EGR-1 overexpression causes enhanced tumor gro wth and that WT1 and EGR-1 exert antagonizing effects on growth regulation in baby rat kidney cells, which might reflect the situation in some Wilms' tumors.