Function of Nuclear Co-repressor Protein on Thyroid Hormone Response Elements Is Regulated by the Receptor A/B Domain

Anthony N Hollenberg,Tsuyoshi Monden,John P Madura,Karen Lee,Fredric E Wondisford

doi:10.1074/jbc.271.45.28516

Anthony N Hollenberg, Tsuyoshi Monden + Show 3 more

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https://doi.org/10.1074/jbc.271.45.28516

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Journal: The Journal of biological chemistry	Publication Date: Nov 1, 1996
Citations: 99	License type: cc-by

Abstract

Recently, a family of nuclear co-repressor proteins (TRACs) have been identified that interact with thyroid hormone (TR) and retinoic acid receptors to mediate ligand-independent repression of gene transcription. In this report, we have cloned and characterized a human TRAC, which when expressed as a truncated protein lacking its repressing domains, can abolish endogenous cellular TRAC activity. Use of this inhibitor has uncovered a differential function of TRACs on negative versus positive thyroid hormone response elements and has demonstrated the importance of the TR A/B domain in modulating TRAC function. Thus, isoform-specific functions of the TR may be mediated by their functional interaction with co-repressor proteins.

Highlights

The thyroid hormone receptor (TR),1 a member of the steroid/ thyroid hormone receptor superfamily, mediates gene regulation through its ability to bind to specific thyroid hormone response elements (TREs) [1,2,3,4] either as a monomer, homodimer, or as a heterodimer with RXR isoforms [5,6,7]
As this original clone contained the interacting domain of NCoR and surrounding amino acids (AA 1539 – 2453), but lacked the two repressor domains present between AA 1–1120 of murine NCoR, we hypothesized that it would function as a dominant inhibitor of endogenous termed nuclear co-repressors (TRAC) activity and termed it, NCoRI
As we have demonstrated previously, TR␣1 is a more potent ligand-independent repressor than TR␤1 on positive TREs

Summary

Introduction

The thyroid hormone receptor (TR),1 a member of the steroid/ thyroid hormone receptor superfamily, mediates gene regulation through its ability to bind to specific thyroid hormone response elements (TREs) [1,2,3,4] either as a monomer, homodimer, or as a heterodimer with RXR isoforms [5,6,7]. We report that this portion of NCoR functions as a powerful dominant inhibitor of endogenous cellular co-repressor activity on TREs and substantially increases ligand-dependent negative regulation by the TR␤1 and ␣1 isoforms.

Results

Conclusion