Early growth response 1 acts as a tumor suppressor in vivo and in vitro via regulation of p53.
The early growth response 1 (Egr1) gene is a transcription factor that acts as both a tumor suppressor and a tumor promoter. Egr1-null mouse embryo fibroblasts bypass replicative senescence and exhibit a loss of DNA damage response and an apparent immortal growth, suggesting loss of p53 functions. Stringent expression analysis revealed 266 transcripts with >2-fold differential expression in Egr1-null mouse embryo fibroblasts, including 143 known genes. Of the 143 genes, program-assisted searching revealed 66 informative genes linked to Egr1. All 66 genes could be placed on a single regulatory network consisting of three branch points of known Egr1 target genes: TGFbeta1, IL6, and IGFI. Moreover, 19 additional genes that are known targets of p53 were identified, indicating that p53 is a fourth branch point. Electrophoretic mobility shift assay as well as chromatin immunoprecipitation confirmed that p53 is a direct target of Egr1. Because deficient p53 expression causes tumors in mice, we tested the role of Egr1 in a two-step skin carcinogenesis study (144 mice) that revealed a uniformly accelerated development of skin tumors in Egr1-null mice (P < 0.005). These studies reveal a new role for Egr1 as an in vivo tumor suppressor.
Krones-Herzig
Anja
A
Sidney Kimmel Cancer Center, San Diego, California 92121, USA.
Mittal
Shalu
S
Yule
Kelly
K
Liang
Hongyan
H
English
Chris
C
Urcis
Rafael
R
Soni
Tarun
T
Adamson
Eileen D
ED
Mercola
Dan
D
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D048708:Cell Growth Processes / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002874:Chromosome Mapping; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051766:Early Growth Response Protein 1; D005260:Female; D005347:Fibroblasts / Q000502:physiology; D020869:Gene Expression Profiling; D016147:Genes, Tumor Suppressor; D017874:Immediate-Early Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics*; D013755:Tetradecanoylphorbol Acetate; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation
D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D017874:Immediate-Early Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D015127:9,10-Dimethyl-1,2-benzanthracene; D013755:Tetradecanoylphorbol Acetate