EGR-1 NEGATIVELY REGULATES HUMAN TUMOR-CELL GROWTH VIA THE DNA-BINDING DOMAIN

Human HT1080 fibrosarcoma cells, subclone H4, express little or no Egr -1 (Zif/268, Krox 24), an early growth response gene encoding a transc ription factor. Phorbol ester (but not serum) treatment only can elici t a small increase in Egr-1 expression in H4, in contrast to the norma lly rapid, high transient expression of Egr-1 observed after the addit ion of a wide range of stimulating agents to normal or immortalized ce ll lines. Because several human tumor cell lines express little Egr-1, we tested the hypothesis that this loss was causal to transformation. We report here that the expression of exogenous mouse Egr-1 in H4 cel ls inhibits transformed growth in a dose-dependent manner and signific antly suppresses tumorigenicity in athymic mice. By overexpression of the fragment in Egr-1 that is responsible for its DNA-binding activity , the zinc-finger domain, we show that this domain has a similar activ ity. Moreover, the expression of antisense mRNA encoding the DNA-bindi ng domain increases the transformed character of the H4 cells. One pos sible conclusion is that endogenous Egr-1-like genes perform growth-re gulatory functions. Other human tumor lines are also growth suppressed by Egr-1 overexpression including ZR-75-1 breast carcinoma, U251 glio blastoma, and to a lesser extent, SAOS-2 osteosarcoma cells. These res ults are surprising in light of the ''early growth response'' characte r of Egr-1 but extend our earlier report of suppression of growth in v -sis-transformed NIH3T3 cells.