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Crosstalk Between Oestrogen Receptors and Thyroid Hormone Receptor Isoforms Results in Differential Regulation of the Preproenkephalin Gene
Author(s) -
Vasudevan N.,
Zhu Y.S.,
Daniel S.,
Koibuchi N.,
Chin W. W.,
Pfaff D.
Publication year - 2001
Publication title -
journal of neuroendocrinology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.062
H-Index - 116
eISSN - 1365-2826
pISSN - 0953-8194
DOI - 10.1046/j.1365-2826.2001.00693.x
Subject(s) - transactivation , coactivator , gene isoform , estrogen receptor alpha , nuclear receptor , receptor , endocrinology , medicine , transfection , biology , gene expression , thyroid hormone receptor , chemistry , transcription factor , microbiology and biotechnology , estrogen receptor , gene , hormone , biochemistry , cancer , breast cancer
Nuclear receptors are ligand‐activated transcription factors, which have the potential to integrate internal metabolic events in an organism, with consequences for control of behaviour. Previous studies from this laboratory have shown that thyroid hormone receptor (TR) isoforms can inhibit oestrogen receptor (ER)α‐mediated induction of preproenkephalin (PPE) gene expression in the hypothalamus. Also, thyroid hormone administration inhibits lordosis, a behaviour facilitated by PPE expression. We have examined the effect of multiple ligand‐binding TR isoforms on the ER‐mediated induction of the PPE gene in transient transfection assays in CV‐1 cells. On a natural PPE gene promoter fragment containing two putative oestrogen response elements (EREs), both ERα and β isoforms mediate a four to five‐fold induction by oestrogen. Cotransfection of TRα1 along with ERα inhibited the ERα transactivation of PPE by approximately 50%. However, cotransfection with either TRβ1 or TRβ2 expression plasmids produced no effect on the ERα or ERβ mediated induction of PPE. Therefore, under these experimental conditions, interactions with a single ER isoform are specific to an individual TR isoform. Transfection with a TRα1 DNA‐binding mutant could also inhibit ERα transactivation, suggesting that competition for binding on the ERE may not be the exclusive mechanism for inhibition. Data with the coactivator, SRC‐1, suggested that coactivator squelching may participate in the inhibition. In dramatic contrast, when ERβ is cotransfected, TRα1 stimulated ERβ‐mediated transactivation of PPE by approximately eight‐fold over control levels. This is the first study revealing specific interactions among nuclear receptor isoforms on a neuroendocrine promoter. These data also suggest that the combinatorics of ER and TR isoforms allow multiple forms of flexible gene regulations in the service of neuroendocrine integration.