Abstract
Thyroid hormones are thought to modulate gene expression positively or negatively through interactions with chromatin-associated receptors1. Recently, the c-erbA proto–oncogene products have been shown to be nuclear thyroid hormone (T3) receptors (TR)2–5 by sequence similarity with other steroid receptors and by their ability to bind thyroid hormone. But it has not been shown that these receptors directly activate transcription of the responsive genes in vivo. In addition, the rat TRα gene encodes several messenger RNA (mRNA) species, generated by differential processing of its transcripts (ref. 22). For these reasons we investigated the ability of two major isoforms of the rat TRa gene products to activate transcription of a sarcomeric myosin heavy chain (mHC) gene, because expression of all members of this gene family is responsive to T63. We show here that the rTRα1 receptor is a thyroid hormone-dependent transcriptional factor, which upon binding the T3 responsive element of the α-mHC gene, activates expression of this gene in vivo. The rTRα2 isoform, which is identical to rTRα1 except for its carboxyl terminal portion, is generated by alternative splicing of the rTRα gene transcript. This peptide, when produced in vitro and in vivo failed to bind T3 or other hormones or to trans-activate α-mHC gene expression. Thus, alternative splicing can produce marked differences in the functional properties of a transcriptional factor.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Openheimer, J. H. & Samuels, H. H. (eds) Molecular Basis of Thyroid Hormone Action (Academic, London, 1983).
Sap, J. et al. Nature 24, 635–640 (1986).
Weinberger, C. et al. Nature 324, 641–646 (1986).
Thompson, C. C., Weinberger, C., Lebo, R. & Evans, R. M. Science 237, 1610–1614 (1987).
Benbrook, D. & Pfahl, M. Science 238, 788–791 (1987).
Izumo, S., Nadal-Ginard, B. & Mahdavi, V. Science 231, 597–600 (1986).
Green, S. & Chambon, P. Nature 324, 615–617 (1986).
Robertson, M. Nature 330, 420–421 (1987).
Pfahl, M. & Bendrook, D. Nucleic Acids Res. 15, 9613 (1987).
Glass, C. K. et al. Nature 320, 738–741 (1987).
Maniatis, T., Fritsch, E. F. & Sambrook, J. Molecular Cloning: A Laboratory Manual (Cold Spring Harbor Laboratory, New York, 1982).
Feinberg, A. P. & Vogelstein, B. Analyt. Biochem. 132, 6–13 (1983).
Sanger, F., Nicklen, S. & Coulson, A. R. Proc. natn. Acad. Sci. U.S.A. 74, 5436–5440 (1977).
Inoue, A., Yamakawa, J., Yukioka, M. & Morisawa, S. Analyt. Biochem. 134, 176–183 (1983).
Dignam, J. M., Lebovitz, R. M. & Roeder, R. G. Nucleic Acids Res. 11, 1475–1489 (1983).
Southern, P. J. & Berg, P. J. Molec. Appl. Genet. 1, 327–341 (1982).
Bouvagnet, P. F. et al. Molec. cell. Biol. 7, 4377–4389 (1987).
Mahdavi, V., Chambers, A. P. & Nadal-Ginard, B. Proc. natn. Acad. Sci. U.S.A. 81, 2626–2630 (1984).
Gorman, C. M., Moffat, F. & Howard, B. H. Molec. cell. Biol. 2, 1044–1051 (1982).
Samuels, H. H., Stanley, F. & Casanova, J. Endocrinology 105, 80–85 (1979).
Neumann, J. R., Morency, C. A. & Russian, K. O. Bio-Techniques 5, 444–447 (1987).
Izumo, S., Tsika, R. & Mahdavi, V. J. biol. Chem. (submitted).
Mahdavi, V. et al. in Cellular and Molecular Biology of Muscle Development (ed. Stockdale, F. & Kedes, L) (Liss, New York, in the press).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Izumo, S., Mahdavi, V. Thyroid hormone receptor α isoforms generated by alternative splicing differentially activate myosin HC gene transcription. Nature 334, 539–542 (1988). https://doi.org/10.1038/334539a0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/334539a0
This article is cited by
-
Early dysregulation of cardiac-specific microRNA-208a is linked to maladaptive cardiac remodelling in diabetic myocardium
Cardiovascular Diabetology (2019)
-
Skeletal Effects of Thyroid Hormones
Clinical Reviews in Bone and Mineral Metabolism (2018)
-
Thyroid hormone receptor α in breast cancer: prognostic and therapeutic implications
Breast Cancer Research and Treatment (2015)
-
Thyroid hormone action in metabolic regulation
Protein & Cell (2011)
-
Structure and expression of two nuclear receptor genes in marsupials: insights into the evolution of the antisense overlap between the α-thyroid hormone receptor and Rev-erbα
BMC Molecular Biology (2010)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.