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The adenovirus E4orf6 protein can promote E1A/E1B-induced focus formation by interfering with p53 tumor suppressor
M Nevels1, S Rubenwolf, T Spruss
1Institut für Medizinische Mikrobiologie und Hygiene, Universität Regensburg, Germany.
Abstract:
We have recently shown that the adenovirus type 5 E4orf6 protein interacts with the cellular tumor suppressor protein p53 and blocks p53 transcriptional functions. Here we report that the E4orf6 protein can promote focus formation of primary rodent epithelial cells in cooperation with adenovirus E1A and E1A plus E1B proteins. The E4orf6 protein can also inhibit p53-mediated suppression of E1A plus E1B-19kDa-induced focus formation. Mutant analysis of the E4orf6 protein demonstrates that these activities correlate with the ability of the adenovirus protein to relieve transcriptional repression mediated by the carboxyl-terminal region of p53 in transient transfection assays. We further demonstrate that expression of wild-type E4orf6 correlates with a dramatic reduction of p53 steady-state levels in transformed rat cells. Our data demonstrate that adenovirus type 5 encodes two different proteins, E1B-55kDa and E4orf6, that bind to p53 and contribute to transformation by modulating p53 transcriptional functions.
Insights
Adenovirus type 5 E4orf6 protein interacts with tumor suppressor p53, blocking its functions. This interaction promotes cell transformation by modulating p53 activity, highlighting a key viral mechanism in oncogenesis.
Area of Science:
- Molecular Biology
- Virology
- Oncology
Background:
- The adenovirus type 5 E4orf6 protein is known to interact with the cellular tumor suppressor protein p53.
- This interaction has been shown to inhibit p53's transcriptional functions.
Purpose of the Study:
- To investigate the role of adenovirus type 5 E4orf6 protein in cellular transformation.
- To elucidate the mechanism by which E4orf6 modulates p53 transcriptional functions.
Main Methods:
- Focus formation assays using primary rodent epithelial cells.
- Mutant analysis of the E4orf6 protein.
- Transient transfection assays to assess transcriptional repression.
- Analysis of p53 steady-state levels in transformed rat cells.
Main Results:
- E4orf6 protein promotes focus formation in cooperation with adenovirus E1A and E1A plus E1B proteins.
- E4orf6 inhibits p53-mediated suppression of focus formation.
- Mutant analysis revealed that E4orf6's activity correlates with relieving p53 carboxyl-terminal repression.
- Wild-type E4orf6 expression leads to a significant reduction in p53 levels in transformed rat cells.
Conclusions:
- Adenovirus type 5 encodes two proteins, E1B-55kDa and E4orf6, that bind to p53.
- These viral proteins contribute to cell transformation by modulating p53 transcriptional functions.
- The study elucidates a mechanism of viral oncogenesis involving p53 pathway disruption.