The role of thyroid hormone receptor DNA binding in negative thyroid hormone-mediated gene transcription.
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The role of thyroid hormone receptor DNA binding in negative thyroid hormone-mediated gene transcription. / Wulf, Anne; Wetzel, Marianne G; Kebenko, Maxim; Kröger, Meike; Harneit, Angelika; Merz, Jennifer; Weitzel, Joachim M.
In: J MOL ENDOCRINOL, Vol. 41, No. 1, 1, 2008, p. 25-34.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - The role of thyroid hormone receptor DNA binding in negative thyroid hormone-mediated gene transcription.
AU - Wulf, Anne
AU - Wetzel, Marianne G
AU - Kebenko, Maxim
AU - Kröger, Meike
AU - Harneit, Angelika
AU - Merz, Jennifer
AU - Weitzel, Joachim M
PY - 2008
Y1 - 2008
N2 - Thyroid hormone 3,3',5-tri-iodothyronine (T3) regulates gene expression in a positive and negative manner. Here, we analyzed the regulation of a positively (mitochondrial glycerol-3-phosphate dehydrogenase) and negatively T3-regulated target gene (TSHalpha). Thyroid hormone receptor (TR) activates mGPDH but not TSH promoter fragments in a mammalian one-hybrid assay. Furthermore, we investigated functional consequences of targeting TR to DNA independent of its own DNA-binding domain (DBD). Using a chimeric fusion protein of the DBD of yeast transcription factor Gal4 with TR, we demonstrated a positive regulation of gene transcription in response to T3. T3-mediated activation of this chimeric protein is further increased after an introduction of point mutations within the DBD of TR. Moreover, we investigated the capacity of TR to negatively regulate gene transcription on a DNA-tethered cofactor platform. A direct binding of TR to DNA via its own DBD is dispensable in this assay. We investigated functional consequences of point mutations affecting different domains of TR. Our data indicate that the DBD of TR plays a key role in direct DNA binding on positively but not on negatively T3-regulated target genes. Nevertheless, the DBD is involved in mediating negative gene regulation independent of its capacity to bind DNA.
AB - Thyroid hormone 3,3',5-tri-iodothyronine (T3) regulates gene expression in a positive and negative manner. Here, we analyzed the regulation of a positively (mitochondrial glycerol-3-phosphate dehydrogenase) and negatively T3-regulated target gene (TSHalpha). Thyroid hormone receptor (TR) activates mGPDH but not TSH promoter fragments in a mammalian one-hybrid assay. Furthermore, we investigated functional consequences of targeting TR to DNA independent of its own DNA-binding domain (DBD). Using a chimeric fusion protein of the DBD of yeast transcription factor Gal4 with TR, we demonstrated a positive regulation of gene transcription in response to T3. T3-mediated activation of this chimeric protein is further increased after an introduction of point mutations within the DBD of TR. Moreover, we investigated the capacity of TR to negatively regulate gene transcription on a DNA-tethered cofactor platform. A direct binding of TR to DNA via its own DBD is dispensable in this assay. We investigated functional consequences of point mutations affecting different domains of TR. Our data indicate that the DBD of TR plays a key role in direct DNA binding on positively but not on negatively T3-regulated target genes. Nevertheless, the DBD is involved in mediating negative gene regulation independent of its capacity to bind DNA.
M3 - SCORING: Zeitschriftenaufsatz
VL - 41
SP - 25
EP - 34
JO - J MOL ENDOCRINOL
JF - J MOL ENDOCRINOL
SN - 0952-5041
IS - 1
M1 - 1
ER -