Thyroid hormone receptors repress estrogen receptor activation of a TRE.
The identification of hormone response elements in the promoter regions of hormonally regulated genes has revealed a striking similarity between the estrogen response element (ERE) and a palindromic thyroid hormone response element (TRE) derived from the GH gene promoter. In addition, this TRE was described as a strong retinoic acid receptor response element for all three subtypes: alpha, beta, and gamma. We show here that the TRE in the absence of thyroid hormone receptor (TR) behaves similarly to imperfect EREs, which can synergize to mediate a strong estrogen-dependent activation of transcription. However, in the presence of TR, but the absence of T3, activation of the TRE constructs by estrogen receptor (ER) is inhibited. In vitro, ER and TR were found to bind to the TRE in the absence and presence of their respective ligands; however, TRs form a more stable complex with the TRE than does ER. To examine whether repression of ER activity on the TRE constructs by TR was due to heterodimer formation, we employed truncated TR mutants (tTR) that lacked the DNA-binding domain, but contained the ligand-binding/dimerization domain. The tTRs were shown to be efficient inhibitors of TR, but not of ER. Thus, inhibition of ER activity on TREs by TRs does not result from heterodimer formation. We discuss a mechanism in which TRs, in the absence of thyroid hormone, control TRE activation by related receptors by preventing their access to the TRE. This mechanism can greatly enhance the fidelity of the ligand-specific response from a TRE.
Graupner
G
G
La Jolla Cancer Research Foundation, California 92037.
Zhang
X K
XK
Tzukerman
M
M
Wills
K
K
Hermann
T
T
Pfahl
M
M
D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics; D015500:Chloramphenicol O-Acetyltransferase / Q000378:metabolism; D004247:DNA / Q000737:chemistry; D004357:Drug Synergism; D005786:Gene Expression Regulation; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D009154:Mutation; D011401:Promoter Regions, Genetic; D011960:Receptors, Estrogen / Q000235:genetics*; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone / Q000235:genetics*; D014158:Transcription, Genetic; D014162:Transfection; D014212:Tretinoin / Q000378:metabolism
D002352:Carrier Proteins; D008024:Ligands; D011960:Receptors, Estrogen; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D014212:Tretinoin; D004247:DNA; D015500:Chloramphenicol O-Acetyltransferase