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.