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Molecular and Cellular Biology, November 2000, p. 8329-8342, Vol. 20, No. 22
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 TR
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Cloning and Characterization of Two Novel Thyroid
Hormone Receptor
Isoforms
(NR1A1) and TR
(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 TR
isoforms that are expressed widely and
result from alternative mRNA splicing. TR
3 is a 44.6-kDa protein
that contains an unique 23-amino-acid N terminus and acts as a
functional receptor. TR
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
3 and

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.
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