Inhibition of thyroid hormone action by a non-hormone binding c-erbA protein generated by alternative mRNA splicing.
Thyroid hormone (T3) binds to a nuclear receptor protein which regulates gene expression by binding to specific DNA sequences near hormone-responsive genes. Proteins encoded by two cellular proto-oncogenes, c-erbA alpha and beta, bind T3 and can act as functional T3 receptors. In rats, alternative splicing of the alpha-gene transcript generates at least two distinct protein products, termed r-erbA alpha 1 and r-erbA alpha 2. Although these proteins bind to the same DNA sequence, r-erbA alpha 2 does not bind T3. We show here that expression of r-erbA alpha 2 inhibits the T3-dependent inductive effect of either r-erbA beta or r-erbA alpha 1 on expression of a T3-responsive test gene. Alternative splicing of the erbA alpha transcript thus generates products with opposing biological activities, suggesting a novel mechanism for the modulation of hormonal responsiveness.
Koenig
R J
RJ
Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
Lazar
M A
MA
Hodin
R A
RA
Brent
G A
GA
Larsen
P R
PR
Chin
W W
WW
Moore
D D
DD
D000818:Animals; D002460:Cell Line; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics; D005822:Genetic Vectors; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics*; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D014162:Transfection / Q000187:drug effects*; D014284:Triiodothyronine / Q000037:antagonists & inhibitors* / Q000494:pharmacology
D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D011988:Receptors, Thyroid Hormone; D014284:Triiodothyronine; D015500:Chloramphenicol O-Acetyltransferase