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Inhibition of thyroid hormone action by a non-hormone binding c-erbA protein generated by alternative mRNA splicing

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Abstract

Thyroid hormone (T3) binds to a nuclear receptor protein which regulates gene expression by binding to specific DNA sequences near hormone-responsive genes1. Proteins encoded by two cellular proto-oncogenes, c-erbA α and β, bind T32,3 and can act as functional T3 receptors4,5. In rats, alternative splicing of the a-gene transcript generates at least two distinct protein products, termed r-erbAαl and r-erbAα25-7. Although these proteins bind to the same DNA sequence, r-erbAα2 does not bind T3. We show here that expression of r-erbAα2 inhibits the T3-dependent inductive effect of either r-erbAβ or r-erbAαl on expression of a T3-responsive test gene. Alternative splicing of the erbAα transcript thus generates products with opposing biological activities, suggesting a novel mechanism for the modulation of hormonal responsiveness.

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Author notes

  1. Ronald J. Koenig

    Present address: Division of Endocrinology & Metabolism, University of Michigan Medical Center, 1500 East Medical Center Drive, 3920 Taubman Center, Ann Arbor, Michigan, 48109-0354, USA

  2. David D. Moore: To whom correspondence should be addressed at the Massachusetts General Hospital.

Authors and Affiliations

  1. Howard Hughes Medical Institute Laboratories, Thyroid Division, Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, 02115, USA

    Ronald J. Koenig & P. Reed Larsen

  2. Howard Hughes Medical Institute Laboratories, Genetics Division, Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, 02115, USA

    Mitchell A. Lazar, Richard A. Hodin & William W. Chin

  3. Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, 02114, USA

    Gregory A. Brent & David D. Moore

  4. Department of Genetics, Harvard Medical School, Boston, Massachusetts, 02115, USA

    Gregory A. Brent & David D. Moore

Authors
  1. Ronald J. Koenig
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  2. Mitchell A. Lazar
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  3. Richard A. Hodin
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  4. Gregory A. Brent
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  5. P. Reed Larsen
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  6. William W. Chin
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  7. David D. Moore
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Koenig, R., Lazar, M., Hodin, R. et al. Inhibition of thyroid hormone action by a non-hormone binding c-erbA protein generated by alternative mRNA splicing. Nature 337, 659–661 (1989). https://doi.org/10.1038/337659a0

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  • DOI: https://doi.org/10.1038/337659a0

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