EGR-1 induction is required for maximal radiosensitivity in A375-C6 melanoma cells.
Exposure to ionizing radiation leads to induction of the immediate-early gene, early growth response-1 (Egr-1). Previous studies have suggested distinct cell type- and inducer-specific roles for EGR-1 protein in cellular growth inhibition. The present study was undertaken to determine the functional role of EGR-1 in growth inhibition caused by exposure of tumor cells to ionizing radiation. Exposure to ionizing radiation caused induction of EGR-1 protein in human melanoma cells A375-C6. Inhibition of either the function of EGR-1 protein by stable transfection with a dominant-negative mutant or the expression of EGR-1 by transient transfection with an antisense oligomer resulted in a diminished growth-inhibitory response to ionizing radiation. Because previous studies have suggested that mutations in the tumor-suppressor gene p53 confer radio-resistance, we examined the p53 status of A375-C6 cells. Interestingly, both the parental and the transfected A375-C6 cells showed trisomy for wild-type p53 alleles. Exposure to ionizing radiation resulted in induction of p53 protein that localized to the nucleus in A375-C6 cells. These data suggest that inhibition of EGR-1 function confers radio resistance despite the induction of wild-type nuclear p53. Thus, EGR-1 is required for the growth-inhibitory response to ionizing radiation in A375-C6 cells.
Department of Radiation Medicine, University of Kentucky, Lexington, Kentucky 40536, USA.
M M
MM
Ahmed
K
K
Venkatasubbarao
S M
SM
Fruitwala
S
S
Muthukkumar
D P
DP
Wood
S F
SF
Sells
M
M
Mohiuddin
V M
VM
Rangnekar
D002455:Cell Division / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D051766:Early Growth Response Protein 1; D005799:Genes, Dominant; D006801:Humans; D017874:Immediate-Early Proteins; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010641:Phenotype; D011836:Radiation Tolerance; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D017874:Immediate-Early Proteins; D016376:Oligonucleotides, Antisense; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53