nuclear, as expected; however, surprisingly both 
cytoplasmic and nuclear staining were observed for 
the anti-a antibodies, suggesting that the intracellu- 
lar distribution of c-erbAa2 and/or TRal may be 
different than the distribution of TR/3s in the pitu- 
itary. The staining of rat pituitary glands by the anti- 
TR/32 antibodies demonstrates for the first time that 
TR/32 is expressed as a protein in pituitary cells. Fur- 
thermore, the staining of human pituitary glands by 
the anti-TR/32 antibodies suggests that there is a hu- 
man homologue of the rat pituitary-specific TR/32 
that shares similar epitopes with the rat TRj82. Thus 
isoform-specific antibodies against TRs that can rec- 
ognize in vitro translated, transiently transfected, 
and in situ rat and human pituitary TRs have been 
prepared. 
Homo- and Heterodimers 
in Thyroid Hormone Action 
Dr. Chin and others previously showed that TR 
binding to thyroid hormone response elements 
(TREs) can be enhanced by interaction with a nu- 
clear protein, TR auxiliary protein (TRAP). He has 
studied the binding of TRal and TR^Sl to several 
TREs: the chick lysozyme TRE (F2), which is posi- 
tively regulated by T3 (3,5,3'-triiodothyronine); 
rabbit 18-myosin heavy-chain TRE (/3-MHC), which is 
negatively regulated by T3; and an idealized invened 
palindrome, TRElap. The formation of homodimers, 
TRa-TR|S dimers, and TR-TRAP heterodimers when 
receptor is bound to these DNA sequences was dem- 
onstrated. Surprisingly, TH decreased in a dose- 
dependent manner TRal and TR|8l homodimer 
binding to these TREs as well as TRa-TR/3 dimer 
binding to F2 but did not affect TR-TRAP hetero- 
dimer binding to TREs. Recently others have demon- 
strated that retinoid X receptor (RXR) may be a 
TRAP and that, in addition to TRAP and RXR, TR 
heterodimerizes with retinoic acid receptor (RAR) 
on natural and synthetic hormone response ele- 
ments. The effect of TH on TR-RAR and TR-RXR he- 
terodimer binding to DNA was also examined. TR 
formed heterodimers with RAR and RXR on a reti- 
noic acid response element and two TREs. Surpris- 
ingly, TH, but not retinoic acid (RA), decreased TR- 
RAR heterodimer binding to DNA. In contrast, 
neither TH, all-trans RA, or 9-cis RA affected TR- 
RXR binding to DNA. These findings suggest that the 
TR-RXR heterodimer is also, along with TR-TRAP, a 
stable receptor complex that remains bound to re- 
sponse elements in the presence of ligand and there- 
fore may be a receptor complex involved in TH-re- 
gulated transcription. 
Mechanism of Defective TH Signaling 
in the Syndrome of GeneraUzed 
Resistance to TH 
Generalized resistance to TH (GRTH) is a syn- 
drome of hyposensitivity to T3 (TH) that often dis- 
plays autosomal dominant inheritance. The genetic 
defect commonly lies in the ligand-binding domain 
of one of the TRj3 alleles. Since there are two major 
TR isoforms, TRa and TR/3, it is not known how the 
mutant receptor mediates a dominant negative ef- 
fect. The electrophoretic mobility shift assay was 
employed to compare the effect of TH on the DNA 
binding of mutant TR/31 from a kindred with GRTH 
(Mf- 1 ) with TR|8 Mf- 1 bound better as a homodimer 
than TR/3 but dissociated from DNA only at high TH 
concentrations. Both receptors heterodimerized 
with nuclear auxiliary proteins. They also dimerized 
with TRa and with each other. Surprisingly, TH 
disrupted the DNA binding of the Mf- 1 -TR isoform 
dimers. Thus mechanisms for the dominant negative 
effect by mutant TRs likely involve either increased 
binding to TREs by mutant homodimers that cannot 
bind TH (hence cannot dissociate from DNA) and/ 
or the formation of inactive mutant TR-nuclear pro- 
tein heterodimers. 
Dr. Chin is also Associate Professor of Medicine 
at Harvard Medical School, Senior Physician at 
Brigham and Women 's Hospital, and Clinical As- 
sociate in Medicine at Massachusetts General Hos- 
pital, Boston. 
Books and Chapters of Books 
Chin, W.W. 1991. Regulation of pituitary gonado- 
tropin genes. In Frontiers in Reproductive Endo- 
crinology. Boston, MA: Serono Symposia, pp 85- 
90. 
Chin, W.W. 1992. Control of gene expression. In 
Textbook of Internal Medicine (Kelley, W.N., 
Ed.). Philadelphia, PA: Lippincott, 2nd ed, pp 
1927-1929. 
Chin, W.W. 1992. Sequence-specific DNA binding 
proteins. In Introduction to Molecular and Cel- 
lular Biology. Bethesda, MD: Endocrine Society 
Press, pp 37-43. 
Kahn, C.R., Smith, R.J., and Chin, W.W. 1991. 
Mechanism of action of hormones that act at the 
cell surface. In Williams Textbook of Endocri- 
nology (Wilson, J.D., and Foster, D.W., Eds.). 
Philadelphia, PA: Saunders, pp 85-90. 
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