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Identification of a domain required for oncogenic activity and transcriptional suppression by v-erbA and
1Department of Neuroendocrinology, Max Planck Institute of Psychiatry, Munich, Germany.
Abstract:
v-erbA, a mutated version of the chicken thyroid hormone (TH) receptor type alpha, can inhibit hormonal induction of target genes. In addition, v-erbA acts as a constitutive repressor of the basal promoter activity. In vivo, v-erbA can arrest the differentiation of erythroid precursor cells and suppresses transcription of erythrocyte-specific genes. We show that the v-erbA protein of the transformation-defective avian erythroblastosis virus mutant (AEVtd359) fails to suppress basal transcription level and exhibits impaired ability in antagonizing the TH and retinoic acid response. The inactivating mutation is a 1-nt change leading to a Pro-->Arg replacement in the "hinge region" of v-erbA protein. Introducing this mutation in the context of TH receptor alpha selectively inactivates the suppressor function, while hormone-binding and transcriptional-activation properties are unaffected. These data suggest that trans-repression rather than a dominant negative block of TH-receptor or retinoic acid-receptor activation may represent the primary molecular property underlying erbA oncogenesis.
Insights
The v-erbA oncogene, a mutated thyroid hormone receptor, normally represses gene activity. A specific mutation impairs this repression, suggesting trans-repression is key to erbA oncogenesis.
Area of Science:
- Molecular Biology
- Oncology
- Cellular Differentiation
Background:
- The v-erbA oncogene, a mutated chicken thyroid hormone receptor alpha, inhibits gene expression and cell differentiation.
- It functions as a constitutive repressor of basal promoter activity and erythrocyte-specific genes.
Purpose of the Study:
- To investigate the molecular mechanisms underlying v-erbA oncogenesis.
- To determine if impaired transcriptional repression contributes to v-erbA's oncogenic potential.
Main Methods:
- Analysis of a transformation-defective v-erbA mutant (AEVtd359).
- Site-directed mutagenesis to introduce a Pro-->Arg change in the hinge region of v-erbA.
- Assessing transcriptional repression and hormone response antagonism.
Main Results:
- The AEVtd359 v-erbA mutant showed reduced ability to suppress basal transcription and antagonize thyroid hormone (TH) and retinoic acid responses.
- A specific mutation in the hinge region selectively inactivated the suppressor function without affecting hormone binding or activation.
- This mutation, when introduced into TH receptor alpha, impaired its suppressor function.
Conclusions:
- Trans-repression, not a dominant-negative effect, is likely the primary mechanism of v-erbA oncogenesis.
- The hinge region mutation highlights the importance of the suppressor function in erbA-mediated transformation.