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Farsetti

Characterization of myelin basic protein thyroid hormone response element and its function in the context of native and heterologous promoter.

Farsetti A, Desvergne B, Hallenbeck P, Robbins J, Nikodem VM.

J Biol Chem. 1992 Aug 5;267(22):15784-8.

"In this report we have characterized further the myelin basic protein (MBP) gene thyroid hormone response element (TRE) by functional and binding analysis. Mutation and deletion experiments revealed that this TRE, confined to the sequences -184 to -167 of the MBP promoter, is able to function as a classical regulatory element in the context of the native and a heterologous promoter. It is comprised of two regions, containing a motif that is highly conserved among other TREs: AGGACA, arranged as an inverted palindrome. Any mutation within the footprinted region impaired receptor binding and function. Moreover, the deletion of sequences outside of the receptor footprinted region (MBP-TRE-18) resulted in a higher triiodothyronine responsiveness and a concomitant increase in receptor-dependent, hormone-independent repression. Results of transfection assays showed that both receptors alpha and beta elicit indistinguishable triiodothyronine responses when the MBP-TRE functions as a regulator of a heterologous promoter activity. However, a preferential beta receptor transactivation was observed when the MBP-TRE was placed in the context of its native promoter."

Molecular basis of thyroid hormone regulation of myelin basic protein gene expression in rodent brain.

Farsetti A, Mitsuhashi T, Desvergne B, Robbins J, Nikodem VM.

J Biol Chem. 1991 Dec 5;266(34):23226-32. Erratum in: J Biol Chem 1992 Aug 25;267(24):17478.

"Regulation of myelin basic protein (MBP) gene expression by thyroid hormone has been investigated in rodent brain. Quantitation of the 4 major alternatively spliced transcripts by RNase protection assay showed that the individual mRNAs, corresponding to MBP isoforms 21.5, 18.5, 17, and 14 kDa, were decreased from 2- to 17-fold at all ages studied (4-60 days) in hypothyroid animals when compared to euthyroid, but the timing of onset of expression was not altered. MBP mRNA was also reduced in young adult rats thyroidectomized at the age of 5-6 weeks and was restored to normal by thyroxine administration. Nuclear run-off assays showed that the rate of MBP gene transcription is dependent on thyroid state. Co-transfection of MBP (-256/+1)-chloramphenicol acetyltransferase chimeric gene with a plasmid expressing thyroid hormone receptor alpha, and in the presence of 3,5,3'-triiodothyronine, into NIH3T3 or NG108-15, increased chloramphenicol acetyltransferase expression 4-fold. Using a footprinting technique and Spodoptera frugiperda 9 (Sf9) nuclear extract infected with baculovirus expressing TR alpha, we have identified a single DNA-binding site (-186/-163) for the receptor. A part of this region contains the AGGACA sequence found in thyroid hormone-responsive elements of other 3,5,3'-triiodothyronine-regulated genes. Our finding of a specific hormone-receptor interaction with the MBP promoter region is the first direct demonstration of a thyroid hormone-responsive element in a brain-specific gene."

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