Estrogen receptor action through target genes with classical and
alternative response elements
P. J. Kushner, P. Webb, R. M. Uht, M.-M. Liu, and R. H. Price, Jr.
Department of Medicine, University of California,
San Francisco, CA 94115-1640, USA
Abstract: The estrogen receptors alpha and beta (ERa
and ERb) mediate the changes in gene expression
from physiological and environmental estrogens. Early studies identified
classical estrogen response elements (EREs) in the promoter region of
target genes whose expression is regulated by estrogen and to which
the ERs bind via their DNA-binding domain (DBD). EREs in the pituitary
prolactin promoter, for example, mediate an activation by both ERα
and ERβ albeit with different affinities for different ligands.
Full activation in most cell types requires the integrity of the activation
function 2 (AF-2) in the receptors ligand binding domain (LBD), which
is engaged by estrogens and disengaged by tamoxifen, raloxifene, and
other antiestrogens. However, in some cells and ERE contexts, the AF-1
in the ERα amino terminal domain (NTD) is sufficient.
We now know that ERs also regulate expression of target genes that
do not have EREs, but instead have various kinds of alternative response
elements that bind heterologous transcription factors whose activity
is regulated by interactions with ERs. Thus, ERa
activates genes, including collagenase and cyclin D1, an important mediator
of cellular proliferation, by AP-1 and CRE sites, which bind Jun/Fos
or Jun/ATF-2 transcription factors. ERa also
activates gene expression through GC-rich elements that bind the SP1
transcription factor. Finally, we also know that ERs mediate inhibition
of the expression of many genes. In one well-studied instance, ERs counterexpression
of genes involved in the inflammatory response by inhibiting the action
at tumor necrosis factor response elements (TNF-REs) that bind the NFkappaB
transcription factor. ERb is especially efficient
at this inhibition.
ERα activation of AP-1/CRE target genes is of special interest
because of the putative role of these target genes in mediating proliferation.
The AF-1 and AF-2 functions of ERa are both
needed for this activation in most cell types. However, in uterine cells,
the AF-1 function is sufficient. Thus, the antiestrogen tamoxifen, which
allows AF-1, mimics estrogen and drives activation of AP-1/CRE target
genes and proliferation of uterine cells. This estrogen-like action,
which can increase the risk of uterine cancer, complicates the use of
tamoxifen to prevent breast cancer. Surprisingly, ERb
inhibits AP-1/CRE target genes in the presence of estrogen. When both
receptors are present, ERb efficiently opposes
activation by ERa. Moreover, ERb
activates the AP-1/CRE target genes in the presence of antiestrogens
especially so-called "complete" antiestrogens raloxifene, and ICI 182,
780.
We here review the evidence for different kinds of promoter elements
that mediate ER action, for the differential ligand preferences of ERa
and ERb at these different elements, and
the potential mechanisms by which they are mediated. One attractive
strategy for the investigation and comparison of potential environmental
estrogens is to assay their activity in cell culture systems using reporter
genes with simplified promoter elements. Thus, the findings of complexity
in ERa and ERb
activation at different types of response elements needs to be taken
into account in the development and interpretation of assays using simplified
promoter elements systems.
*Report from a SCOPE/IUPAC project: Implication of
Endocrine Active Substances for Human and Wildlife (J. Miyamoto and
J.Burger, editors). Other reports are published in this issue,
pp. 1617-2615.
