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Molecular and Cellular Biology, November 2000, p. 8329-8342, Vol. 20, No. 22
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Cloning and Characterization of Two Novel Thyroid Hormone Receptor beta  Isoforms

Graham R. Williams*

ICSM Molecular Endocrinology Group, Division of Medicine and MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, London W12 ONN, United Kingdom

Received 25 April 2000/Returned for modification 8 June 2000/Accepted 21 August 2000

Thyroid hormone (T3) activates nuclear receptor transcription factors, encoded by the TRalpha (NR1A1) and TRbeta (NR1A2) genes, to regulate target gene expression. Several TR isoforms exist, and studies of null mice have identified some unique functions for individual TR variants, although considerable redundancy occurs, raising questions about the specificity of T3 action. Thus, it is not known how diverse T3 actions are regulated in target tissues that express multiple receptor variants. I have identified two novel TRbeta isoforms that are expressed widely and result from alternative mRNA splicing. TRbeta 3 is a 44.6-kDa protein that contains an unique 23-amino-acid N terminus and acts as a functional receptor. TRDelta beta 3 is a 32.8-kDa protein that lacks a DNA binding domain but retains ligand binding activity and is a potent dominant-negative antagonist. The relative concentrations of beta 3 and Delta beta 3 mRNAs vary between tissues and with changes in thyroid status, indicating that alternative splicing is tissue specific and T3 regulated. These data provide novel insights into the mechanisms of T3 action and define a new level of specificity that may regulate thyroid status in tissue.

* Mailing address: Molecular Endocrinology Group, MRC Clinical Sciences Centre, Hammersmith Hospital, Du Cane Rd., London W12 ONN, United Kingdom. Phone: (44) 0208 383 1383. Fax: (44) 0208 383 8306. E-mail: graham.williams{at}ic.ac.uk.

Molecular and Cellular Biology, November 2000, p. 8329-8342, Vol. 20, No. 22
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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