The zinc finger transcription factor EGR-1 impedes interleukin-1-inducible tumor growth arrest.
Interleukin-1 (IL-1) is a growth arrest signal for diverse human tumor cell lines. We report here that the action of this cytokine in melanoma cells is associated with induction of EGR-1, a zinc finger protein that activates gene transcription. Both growth arrest and EGR-1 are induced via the type I receptor of IL-1. To determine the role of EGR-1 in IL-1 action in melanoma cells, we used a chimera expressing the transrepression domain of the Wilm's tumor gene, WT1, and the DNA binding domain of Egr-1. This chimera competitively inhibited EGR-1-dependent transactivation via the GC-rich DNA binding sequence, indicating that it acted as a functional dominant negative mutant of Egr-1. Melanoma cell lines stably transfected with the dominant negative mutant construct were supersensitive to IL-1 and showed accelerated G0/G1 growth arrest compared with the parental cell line. The effect of the dominant negative mutant construct was mimicked by addition of an antisense Egr-1 oligomer to the culture medium of the parental cells: the oligomer inhibited EGR-1 expression and accelerated the growth-inhibitory response to IL-1. These data imply that EGR-1 acts to delay IL-1-mediated tumor growth arrest.
Sells
S F
SF
Department of Surgery, University of Kentucky, Lexington 40536.
Muthukumar
S
S
Sukhatme
V P
VP
Crist
S A
SA
Rangnekar
V M
VM
D001483:Base Sequence; D001665:Binding Sites; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism*; D051766:Early Growth Response Protein 1; D005786:Gene Expression Regulation; D016162:Genes, Wilms Tumor; D006801:Humans; D017874:Immediate-Early Proteins; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007700:Kinetics; D008545:Melanoma; D008969:Molecular Sequence Data; D016296:Mutagenesis; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D017472:Receptors, Interleukin-1 / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D017874:Immediate-Early Proteins; D007375:Interleukin-1; D016376:Oligonucleotides, Antisense; D017472:Receptors, Interleukin-1; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D014157:Transcription Factors