Creation of an active estrogen-responsive element by a single base change in the flanking sequence of a cellular oncogene: a possible mechanism for hormonal carcinogenesis?
Estrogens are considered to act as promoters in a multistep process of hormonal carcinogenesis, although the molecular mechanisms by which these hormones act in tumorigenesis are unclear at present. Estradiol is known to induce expression of certain proto-oncogenes, and this led us to examine potential regulatory regions of the cellular c-fos oncogene. The 5'-flanking region of the murine c-fos contains a 13-bp palindromic sequence (GGTCTnnnAGACC) with striking homology to the consensus estrogen-responsive element (ERE) GGTCAnnnTGACC. However, the c-fos sequence did not bind the human estrogen receptor or confer hormonal responsiveness in a yeast-based transcriptional test system. Importantly, a single base change in the fifth position of the c-fos sequence (GGTCTnnnAGACC to GGTCA/GnnnAGACC) produced an element that bound the estrogen receptor and conferred estrogen-dependent transcriptional activation of a reporter gene. This suggests a specific hypothesis by which estrogens could act as tumor promoters. In this paradigm, the regulatory region of the cellular oncogenes, tumor suppressor genes, and growth-factor genes contain inactive sequences with close homologies to hormone-responsive elements. Initiation occurs when some agent (e.g., a chemical carcinogen) causes a mutation in such a sequence to create a functional hormone-responsive element. Estrogens, acting through their receptors and the mutated element, can then activate the target gene to stimulate cell proliferation and increase the population of initiated cells.
Nawaz
Z
Z
Department of Cell Biology, Baylor College of Medicine, Houston, Texas.
Stancel
G M
GM
McDonnell
D P
DP
Hyder
S M
SM
D000818:Animals; D001483:Base Sequence; D002273:Carcinogens / Q000633:toxicity; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004252:DNA Mutational Analysis; D004271:DNA, Fungal / Q000187:drug effects; D004268:DNA-Binding Proteins; D004967:Estrogens / Q000633:toxicity*; D015972:Gene Expression Regulation, Neoplastic; D005800:Genes, Fungal / Q000187:drug effects*; D016762:Genes, fos / Q000187:drug effects*; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000378:metabolism; D015345:Oligonucleotide Probes; D010957:Plasmids; D017354:Point Mutation; D011960:Receptors, Estrogen / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000187:drug effects*; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D014819:Vitellogenins / Q000235:genetics
D002273:Carcinogens; D004271:DNA, Fungal; D004268:DNA-Binding Proteins; D004967:Estrogens; D009838:Oligodeoxyribonucleotides; D015345:Oligonucleotide Probes; D011960:Receptors, Estrogen; D014819:Vitellogenins