The autoregulatory and tissue-specific activation of gene expression by estrogen receptor
Barton, Michelle Craig
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Permalink
https://hdl.handle.net/2142/20470
Description
Title
The autoregulatory and tissue-specific activation of gene expression by estrogen receptor
Author(s)
Barton, Michelle Craig
Issue Date
1989
Doctoral Committee Chair(s)
Shapiro, David J.
Department of Study
Biochemistry
Discipline
Biochemistry
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Biology, Molecular
Language
eng
Abstract
A single, transient dose of estradiol-17$\beta$ is sufficient to elicit the permanent induction of hepatic estrogen receptor mRNA, which is induced 18-fold, from 0.13 molecules/cell to 2.4 molecules/cell, and then remains fully induced for at least 125 days. In primary liver cultures, extremely low concentrations of estradiol-17$\beta$, which are below the K$\sb{\rm d}$ of the Xenopus laevis estrogen receptor, maintain persistent induction of estrogen receptor mRNA, but not of estrogen-inducible vitellogenin mRNA. This data, and the ability of the antiestrogen, hydroxytamoxifen, to reverse persistent induction of estrogen receptor mRNA, support a model in which transient doses of estradiol-17$\beta$ induce the estrogen receptor and thereby establish an autoregulatory loop. The low levels of estradiol-17$\beta$ normally circulating in male Xenopus laevis and the elevated level of receptor provide sufficient hormone-receptor complex to permanently maintain the induced level of expression of the estrogen receptor gene. The irreversible induction of the estrogen receptor may be the regulatory switch which results in the persistent expression of a recently identified class of proteins which exhibit long-term responses to estrogen.
Introduction of the high-affinity Xenopus estrogen receptor by transient transfection of Xenopus tissue culture cells is sufficient for the activation of the endogenous genomic target vitellogenin and estrogen receptor promoters, but does not dictate tissue-specificity. Activation of endogenous, silent, estrogen-regulated promoters occurs to a measurable degree in both target hepatic cells and nontarget fibroblast cells. There is a marked difference in the level of expression between the two cell types, with the hepatic cells displaying a 10-fold higher estrogen-inducible level of vitellogenin RNA post-transfection. Cotransfection of the estrogen receptor and the vitellogenin promoter on extrachromosomal elements reveals no tissue-specific effect. Thus, trans-acting factors which determine tissue-selectivity must be active only when target promoters are integrated into the genome of the cell.
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