Dissection of the C-terminal region of E1A redefines the roles of CtBP and other cellular targets in oncogenic transformation

Research output: Contribution to journalArticle

Authors

  • M. J. Cohen
  • A. F. Yousef
  • P. Massimi
  • G. J. Fonseca
  • B. Todorovic
  • P. Pelka
  • L. Banks
  • J. S. Mymryk

Colleges, School and Institutes

External organisations

  • University of Western Ontario
  • International Centre for Genetic Engineering and Biotechnology
  • University of Manitoba

Abstract

Human adenovirus E1A makes extensive connections with the cellular protein interaction network. By doing so, E1A can manipulate many cellular programs, including cell cycle progression. Through these reprogramming events, E1A functions as a growth-promoting oncogene and has been used extensively to investigate mechanisms contributing to oncogenesis. Nevertheless, it remains unclear how the C-terminal region of E1A contributes to oncogenic transformation. Although this region is required for transformation in cooperation with E1B, it paradoxically suppresses transformation in cooperation with activated Ras. Previous analysis has suggested that the interaction of E1A with CtBP plays a pivotal role in both activities. However, some C-terminal mutants of E1A retain CtBP binding and yet exhibit defects in transformation, suggesting that other targets of this region are also necessary. To explore the roles of these additional factors, we performed an extensive mutational analysis of the C terminus of E1A. We identified key residues that are specifically required for binding all known targets of the C terminus of E1A. We further tested each mutant for the ability to both localize to the nucleus and transform primary rat cells in cooperation with E1B-55K or Ras. Interaction of E1A with importin α3/Qip1, dual-specificity tyrosine-regulated kinase 1A (DYRK1A), HAN11, and CtBP influenced transformation with E1B-55K. Interestingly, the interaction of E1A with DYRK1A and HAN11 appeared to play a role in suppression of transformation by activated Ras whereas interaction with CtBP was not necessary. This unexpected result suggests a need for revision of current models and provides new insight into transformation by the C terminus of E1A.

Details

Original languageEnglish
Pages (from-to)10348-10355
Number of pages8
JournalJournal of virology
Volume87
Issue number18
Publication statusPublished - 5 Sep 2013

ASJC Scopus subject areas