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

Sangho Lee, Martin L. Privalsky

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)6737-6752
Number of pages16
JournalOncogene
Volume24
Issue number45
DOIs
StatePublished - Oct 13 2005

Fingerprint

Co-Repressor Proteins
Oncogene Proteins
Viral Proteins
Mutation
Hormones
Alpharetrovirus
Amino Acids
Dimerization
Thyroid Hormones
Carrier Proteins
Transcription Factors
Genes
Proteins

Keywords

  • c-Erb A
  • c-Jun
  • Dominant negative
  • T3R
  • Thyroid hormone receptor
  • v-Erb A

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Multiple mutations contribute to repression by the v-Erb A oncoprotein. / Lee, Sangho; Privalsky, Martin L.

In: Oncogene, Vol. 24, No. 45, 13.10.2005, p. 6737-6752.

Research output: Contribution to journalArticle

Lee, Sangho ; Privalsky, Martin L. / Multiple mutations contribute to repression by the v-Erb A oncoprotein. In: Oncogene. 2005 ; Vol. 24, No. 45. pp. 6737-6752.
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