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Repression of transcription mediated at a thyroid hormone response element by the v-erb-A oncogene product
Abstract:
Several recent observations, such as the identification of the cellular homologue of the v-erb-A oncogene as a thyroid-hormone receptor, have strongly implicated nuclear oncogenes in transcriptional control mechanisms. The v-erb-A oncogene blocks the differentiation of erythroid cells, and changes the growth requirements of fibroblasts and erythroblasts. Mutations in v-erb-A protein have led to the loss of its affinity for thyroid hormones but do not affect its DNA-binding ability, a property required for biological activity. We report here the identification of a novel thyroid-hormone response element (TRE) in the long terminal repeat of Moloney murine leukaemia virus that binds the c-erb-A-alpha protein. The v-erb-A protein abolishes the responsiveness of this TRE to thyroid hormone, although it has a lower affinity than the normal receptor for the TRE. The data indicate that overexpressed v-erb-A protein negatively interferes with normal transcriptional-control mechanisms, and that amino-acid substitutions have altered its DNA-binding properties.
Insights
Nuclear oncogenes like v-erb-A are implicated in transcriptional control. This study identifies a novel thyroid-hormone response element (TRE) affected by v-erb-A, revealing its interference with normal cellular processes.
Area of Science:
- Molecular Biology
- Oncology
- Endocrinology
Background:
- Nuclear oncogenes, including the cellular homologue of v-erb-A, are increasingly recognized for their roles in transcriptional regulation.
- The v-erb-A oncogene is known to disrupt cellular differentiation and alter growth factor requirements in various cell types.
Purpose of the Study:
- To identify and characterize novel thyroid-hormone response elements (TREs) involved in transcriptional control.
- To investigate the interaction of the c-erb-A-alpha protein and the v-erb-A protein with identified TREs.
- To elucidate the mechanism by which v-erb-A protein interferes with thyroid hormone-mediated transcriptional regulation.
Main Methods:
- Identification of a novel TRE within the long terminal repeat of Moloney murine leukemia virus.
- Analysis of the binding affinity of c-erb-A-alpha and v-erb-A proteins to the identified TRE.
- Assessment of the effect of v-erb-A protein on thyroid hormone responsiveness of the TRE.
Main Results:
- A novel TRE that binds the c-erb-A-alpha protein was identified in the Moloney murine leukemia virus LTR.
- The v-erb-A protein binds to this TRE with lower affinity compared to the normal receptor but abolishes thyroid hormone responsiveness.
- Mutations in v-erb-A protein affect its DNA-binding properties and thyroid hormone affinity, impacting its biological activity.
Conclusions:
- Overexpressed v-erb-A protein negatively interferes with normal transcriptional control mechanisms.
- Alterations in amino acid sequences of v-erb-A protein modify its DNA-binding properties and receptor function.
- These findings highlight the critical role of specific TREs and receptor-DNA interactions in oncogenic transformation and cellular regulation.