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Human carboxyl-terminal variant of alpha-type c-erbA inhibits trans-activation by thyroid hormone receptors without
Abstract:
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.
Insights
Human and rat c-erbA alpha-2 variants do not bind thyroid hormone (T3). However, both forms inhibit T3 action, suggesting a general regulatory mechanism for T3 signaling.
Area of Science:
- Endocrinology
- Molecular Biology
- Genetics
Background:
- Thyroid hormone receptors (TRs), including those related to the viral oncogene v-erbA, mediate thyroid hormone (T3) actions.
- The carboxyl-terminal variant c-erbA alpha-2 has controversial roles, with human forms suggested as T3 receptors and rat forms as T3 action inhibitors.
Purpose of the Study:
- To compare the properties of human c-erbA alpha-2 with its rat homolog and other c-erbA forms.
- To clarify the T3-binding and functional activity of human and rat c-erbA alpha-2 variants.
Main Methods:
- Synthesis of c-erbA alpha-2 variants in reticulocyte lysates and mammalian cells.
- Assessment of T3 binding affinity.
- Evaluation of effects on T3-responsive gene expression.
- Comparison of inhibitory effects on T3 action.
Main Results:
- Neither human nor rat c-erbA alpha-2 binds T3 with high affinity.
- Neither variant enhances the expression of T3-responsive genes.
- Both human and rat c-erbA alpha-2 inhibit T3 action mediated by T3-receptor forms of c-erbA.
Conclusions:
- Human c-erbA alpha-2 functions similarly to its rat homolog, acting as an inhibitor of T3 action.
- The modulation of T3 action by endogenous inhibitors related to T3 receptors is likely a conserved regulatory mechanism.