Human carboxyl-terminal variant of alpha-type c-erbA inhibits trans-activation by thyroid hormone receptors without binding thyroid hormone.
Multiple thyroid hormone (T3; L-3,3',5-triiodothyronine) receptors related to the viral oncogene v-erbA have been identified in mammalian tissues and have been shown to mediate certain actions of T3. The role of a carboxyl-terminal variant of alpha-type c-erbA (c-erbA alpha-2) is controversial, since the human form has been reported to be a T3 receptor, while the rat form has been shown to not bind T3. In fact, the rat homolog of c-erbA alpha-2 has been reported to be an inhibitor of T3 action. We have compared the properties of human c-erbA alpha-2 with those of its rat homolog and with other forms of c-erbA. Neither form of c-erbA alpha-2 binds T3 with high affinity whether synthesized in reticulocyte lysates or by transient expression in mammalian cells. Also, neither form increases the expression of a T3-responsive gene. However, human c-erbA alpha-2 inhibits T3 action mediated by a T3-receptor form of c-erbA to an extent similar to that of rat c-erbA alpha-2. Our data strongly suggest that human c-erbA alpha-2 has a biological function similar to that of its rat homolog. Thus, the modulation of T3 action by an endogenous inhibitor related to T3 receptors is likely a general regulatory mechanism.
Lazar
M A
MA
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, MA 02115.
Hodin
R A
RA
Chin
W W
WW
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D014644:Genetic Variation; D006801:Humans; D008969:Molecular Sequence Data; D014176:Protein Biosynthesis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D011519:Proto-Oncogenes / Q000187:drug effects; D051381:Rats; D011988:Receptors, Thyroid Hormone / Q000378:metabolism / Q000502:physiology*; D012689:Sequence Homology, Nucleic Acid; D014158:Transcription, Genetic; D014162:Transfection; D014284:Triiodothyronine / Q000378:metabolism / Q000494:pharmacology
D011518:Proto-Oncogene Proteins; D011988:Receptors, Thyroid Hormone; D014284:Triiodothyronine; D003907:Dexamethasone