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Multiple mutations contribute to repression by the v-Erb A oncoprotein

Oncogene volume 24, pages 6737–6752 (2005)Cite this article

Abstract

The v-Erb A oncoprotein of avian erythroblastosis virus is derived from c-Erb A, a hormone-activated transcription factor. Notably, v-Erb A has sustained multiple mutations relative to c-Erb A and functions as a constitutive transcriptional repressor. We report here an analysis of the contributions of these different mutations to v-Erb A function. Our experiments demonstrate that two amino-acid differences between v-Erb A and c-Erb A, located in the ‘I-box,’ alter the dimerization properties of the viral protein, resulting in more stable homodimer formation, increased corepressor binding, and increased target gene repression. An additional amino-acid difference between v- and c-Erb A, located in helix 3 of the hormone binding domain, renders corepressor binding by the viral protein more resistant to release by thyroid hormone. Finally, we report that a C-terminal truncation in v-Erb A not only inhibits exchange of corepressor and coactivator, as previously noted, but also permits v-Erb A to recruit both SMRT and N-CoR corepressors, whereas c-Erb A is selective for N-CoR. The latter two mutations in v-Erb A also impair its ability to suppress c-Jun function in response to T3 hormone. We propose that the acquisition of oncogenic potential by the v-Erb A protein was a multistep process involving a series of mutations that alter the transcriptional repressive properties of the viral protein through multiple mechanisms.

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Acknowledgements

We thank Liming Liu for superb technical assistance and KR Yamamoto for the generous gift of the AP-1-luciferase reporter. This work was supported by Public Health Service/National Institutes of Health award R37-CA53394.

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  1. Division of Biological Sciences, Section of Microbiology, University of California at Davis, One Shields Avenue, Davis, 95616, CA, USA

    Sangho Lee & Martin L Privalsky

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Correspondence to Martin L Privalsky.

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Lee, S., Privalsky, M. Multiple mutations contribute to repression by the v-Erb A oncoprotein. Oncogene 24, 6737–6752 (2005). https://doi.org/10.1038/sj.onc.1208826

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