Mitogen regulated induction of FRA-1 proto-oncogene is controlled by the transcription factors binding to both serum and TPA response elements.
FRA-1, a member of the FOS family of transcription factors, is overexpressed in a variety of human tumors, and contributes to tumor progression. In addition to mitogens, various toxicants and carcinogens persistently induce FRA-1 expression in vitro and in vivo. Although the mitogen induced expression of c-FOS is relatively well understood, it is poorly defined in the case of FRA-1. Our recent analysis of the FRA-1 promoter has shown a critical role for a TRE located at -318 in mediating the TPA-induced expression. The -379 to -283 bp promoter segment containing a critical TRE (-318), however, is insufficient for the induction of FRA-1 promoter. Here, we show that a 40-bp (-276/-237) segment, comprising a TCF binding site and the CArG box (collectively known as serum response element, SRE), and an ATF site, is also necessary for the FRA-1 induction by TPA and EGF. Interestingly, the -283 to +32 bp FRA-1 promoter fragment containing an SRE and an ATF site alone was also insufficient to confer TPA sensitivity to a reporter gene. However, in association with the -318 TRE, the SRE and ATF sites imparted a strong TPA-inducibility to the reporter. Similarly, EGF also required these motifs for the full induction of this gene. Using ChIP assays we show that, in contrast to c-Jun, SRF, Elk1, ATF1 and CREB proteins bind to SRE and ATF sites of the FRA-1 promoter, constitutively. RNAi-mediated knockdown of endogenous SRF, ELK1 and c-JUN protein expression significantly reduced TPA-stimulated FRA-1 promoter activity. Thus, a bipartite enhancer formed by an upstream TRE and the downstream SRE and ATF sites and the cognate factors is necessary and sufficient for the regulation of FRA-1 in response to mitogens.
Adiseshaiah
Pavan
P
Department of Environmental Health Sciences, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MD 21205, USA.
Peddakama
Suneetha
S
Zhang
Qin
Q
Kalvakolanu
Dhanunjaya V
DV
Reddy
Sekhar P
SP
D051696:Activating Transcription Factors; D001798:Blood Proteins / Q000235:genetics / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology; D008934:Mitogens / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D000090063:Proto-Oncogene Mas; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis* / Q000494:pharmacology*; D027602:Serum Response Element; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014157:Transcription Factors / Q000235:genetics / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D000099169:Fos-Related Antigen 1
D051696:Activating Transcription Factors; D001798:Blood Proteins; D008934:Mitogens; D000090063:Proto-Oncogene Mas; D016760:Proto-Oncogene Proteins c-fos; D013755:Tetradecanoylphorbol Acetate; D014157:Transcription Factors; D000099169:Fos-Related Antigen 1; C000715470:MAS1 protein, human; C032975:12-O-tetradeca-2,4,6,8-tetranoylphorbol-13-acetate