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?

Zafar Nawaz, G. M. Stancel, D. P. McDonnell, S. M. Hyder

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)76-82
Number of pages7
JournalMolecular Carcinogenesis
Volume7
Issue number2
StatePublished - Jan 1 1993
Externally publishedYes

Fingerprint

Oncogenes
Estrogens
Carcinogenesis
Nucleic Acid Regulatory Sequences
Hormones
Estrogen Receptors
Carcinogens
Proto-Oncogenes
5' Flanking Region
Tumor Suppressor Genes
Reporter Genes
Transcriptional Activation
Genes
Estradiol
Intercellular Signaling Peptides and Proteins
Yeasts
Cell Proliferation
Mutation
Population

Keywords

  • c-fos
  • Estrogen receptor
  • Estrogen-responsive element
  • Oligodeoxynucleotides
  • Recombinant DNA
  • Yeast

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Biology

Cite this

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? / Nawaz, Zafar; Stancel, G. M.; McDonnell, D. P.; Hyder, S. M.

In: Molecular Carcinogenesis, Vol. 7, No. 2, 01.01.1993, p. 76-82.

Research output: Contribution to journalArticle

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