TY - JOUR
T1 - Induction of Larval tissue resorption in Xenopus laevis tadpoles by the thyroid hormone receptor agonist GC-1
AU - Furlow, J. David
AU - Yang, Ha Yung
AU - Hsu, Mei
AU - Lim, Wayland
AU - Ermio, Davy J.
AU - Chiellini, Grazia
AU - Scanlan, Thomas S.
PY - 2004/6/18
Y1 - 2004/6/18
N2 - A major challenge in understanding nuclear hormone receptor function is to determine how the same ligand can cause very different tissue-specific responses. Tissue specificity may result from the presence of more than one receptor subtype arising from multiple receptor genes or alternative splicing. Recently, high affinity analogs of nuclear receptor ligands have been synthesized that show subtype selectivity. These analogs can greatly facilitate the study of receptor subtype-specific functions in organisms where mutational analysis is problematic or where it is desirable for receptors to be expressed in their normal physiological contexts. We describe here the effects of the synthetic thyroid hormone analog GC-1 on the metamorphosis of the frog Xenopus laevis. The most potent natural thyroid hormone, 3,5,3′-triidothyronine or T3, shows similar binding affinity and transactivation dose-response curves for both thyroid hormone receptor isotypes, designated TRα and TRβ. GC-1, however, binds to and activates TRβ at least an order of magnitude better than it does TRα. GC-1 efficiently induces death and resorption of premetamorphic tadpole tissues such as the gills and the tail, two tissues that strongly induce thyroid hormone receptor β during metamorphosis. GC-1 has less effect on the growth of adult tissues such as the hindlimbs, which express high TRα levels. The effectiveness of GC-1 in inducing tail resorption and tail gene expression correlates with increasing TRβ levels. These results illustrate the utility of subtype selective ligands as probes of nuclear receptor function in vivo.
AB - A major challenge in understanding nuclear hormone receptor function is to determine how the same ligand can cause very different tissue-specific responses. Tissue specificity may result from the presence of more than one receptor subtype arising from multiple receptor genes or alternative splicing. Recently, high affinity analogs of nuclear receptor ligands have been synthesized that show subtype selectivity. These analogs can greatly facilitate the study of receptor subtype-specific functions in organisms where mutational analysis is problematic or where it is desirable for receptors to be expressed in their normal physiological contexts. We describe here the effects of the synthetic thyroid hormone analog GC-1 on the metamorphosis of the frog Xenopus laevis. The most potent natural thyroid hormone, 3,5,3′-triidothyronine or T3, shows similar binding affinity and transactivation dose-response curves for both thyroid hormone receptor isotypes, designated TRα and TRβ. GC-1, however, binds to and activates TRβ at least an order of magnitude better than it does TRα. GC-1 efficiently induces death and resorption of premetamorphic tadpole tissues such as the gills and the tail, two tissues that strongly induce thyroid hormone receptor β during metamorphosis. GC-1 has less effect on the growth of adult tissues such as the hindlimbs, which express high TRα levels. The effectiveness of GC-1 in inducing tail resorption and tail gene expression correlates with increasing TRβ levels. These results illustrate the utility of subtype selective ligands as probes of nuclear receptor function in vivo.
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U2 - 10.1074/jbc.M402847200
DO - 10.1074/jbc.M402847200
M3 - Article
C2 - 15056670
AN - SCOPUS:2942709700
SN - 0021-9258
VL - 279
SP - 26555
EP - 26562
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 25
ER -