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 transcription factor. Phorbol ester (but not serum) treatment only can elicit a small increase in Egr-1 expression in H4, in contrast to the normally rapid, high transient expression of Egr-1 observed after the addition of a wide range of stimulating agents to normal or immortalized cell 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 cells inhibits transformed growth in a dose-dependent manner and significantly 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 activity. Moreover, the expression of antisense mRNA encoding the DNA-binding domain increases the transformed character of the H4 cells. One possible conclusion is that endogenous Egr-1-like genes perform growth-regulatory functions. Other human tumor lines are also growth suppressed by Egr-1 overexpression including ZR-75-1 breast carcinoma, U251 glioblastoma, and to a lesser extent, SAOS-2 osteosarcoma cells. These results are surprising in light of the "early growth response" character of Egr-1 but extend our earlier report of suppression of growth in v-sis-transformed NIH3T3 cells.
Huang
R P
RP
La Jolla Cancer Research Foundation, California 92037, USA.
Liu
C
C
Fan
Y
Y
Mercola
D
D
Adamson
E D
ED
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002455:Cell Division / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004273:DNA, Neoplasm / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051766:Early Growth Response Protein 1; D005354:Fibrosarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D017874:Immediate-Early Proteins; D051379:Mice; D008969:Molecular Sequence Data; D016372:RNA, Antisense / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D016335:Zinc Fingers / Q000235:genetics
D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D017874:Immediate-Early Proteins; D016372:RNA, Antisense; D014157:Transcription Factors