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Metabolic Research Unit (R.M.U., C.M.A., P.W., P.J.K.), Department of Pathology (R.M.U.), School of Medicine, University of California at San Francisco, San Francisco, California 94143
Address all correspondence and requests for reprints to: Peter J. Kushner, Metabolic Research Unit, HSW Room 1141, University of California, San Francisco, San Francisco, California 94143-0540. E-mail: kushner{at}itsa.ucsf.edu
Estrogens and glucocorticoids often act in opposition to regulate
physiological responses. We investigated whether this might reflect the
opposing actions of hormone-bound receptors on target genes regulated
by the AP-1 response element. We performed a series of transfection
experiments in which transcriptional activation, mediated by the AP-1
response element, was reflected in reporter gene activity. As
previously described, we found that estrogens stimulate, whereas the
glucocorticoid dexamethasone (Dex) inhibits, transcription through a
model promoter from the collagenase gene (-73 to +63). This promoter
bears a consensus AP-1 response element. When HeLa cells were treated
with both estradiol and Dex, the steroids counteracted each other’s
transcriptional effects. The amount of transfected estrogen and
glucocorticoid receptors (ER and GR) determined the extent to which Dex
blunted estrogen stimulation or estrogen prevented Dex inhibition. The
ER/GR interaction was observed both in the presence of estradiol and
tamoxifen, which has previously been shown to have estrogen-like action
at an AP-1 response element. The AP-1 family member c-Jun enhanced Dex
inhibition and estradiol stimulation of transcriptional activation.
c-Fos potentiated the effect of cotransfected c-Jun on estradiol
stimulation but not Dex inhibition. The pattern of steroid responses
was retained in the presence of the c-Jun activator phorbol
12-myristate 13-acetate. However, estradiol stimulation was lost in the
presence of the c-Jun activator tumor necrosis factor-
. The
ER/GR/AP-1 response element interaction was present, not only in a cell
line originally derived from a uterine cervical adenocarcinoma (HeLa),
but also in a cell line derived from the hypothalamus (GT1–1). Lastly,
both progesterone receptor types A and B also interacted with the ER at
the AP-1 site. These data indicate that opposing steroid influences can
be mediated at the level of transcription through the AP-1 site and
suggest that the integration of hormone action at this response element
may underlie some of the opposing actions of estrogens and
glucocorticoids or progestins on physiological responses.
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