Specific isoforms of p73 control the induction of cell death induced by the viral proteins, E1A or apoptin

Poramaporn Klanrit, Marcella B. Flinterman, Edward W. Odell, Gerry Melino, Richard Killick, James S. Norris, Mahvash Tavassoli

Research output: Contribution to journalArticle

Abstract

A member of the p53 family, p73, has several isoforms and differentially regulates transcription of genes involved in the control of the cell cycle and apoptosis. We have previously shown efficient and p53-independent, tumor-specific cell death induced by the viral proteins E1A and Apoptin. Here, we demonstrate that the induction of apoptosis by these viral proteins involves activation of TAp73. Both E1A and Apoptin induced expression of endogenous TAp73 and the p53/p73 BH3-only pro-apoptotic target, PUMA, independently of the p53 function. Furthermore, exogenous expression of TAp73 isoforms, particularly TAp73β, sensitized cells to killing by both E1A and Apoptin, while expression of ΔNp73α blocked this activity. Besides, knockout of the p73 regulator, c-Abl, attenuated E1A-induced apoptosis. In accordance with the role of p73 in apoptosis induced by these viral proteins, overexpression of TAp73β strongly induced apoptosis in p53-deficient cancer cells in vitro and in HNSCC xenografts. Using a doxycycline-inducible system, we provide evidence for target selectivity and significant differences in protein stability for specific p73 isoforms, suggesting a diverse and pivotal role for p73 in response to various genotoxic agents. Collectively, our data show that in the absence of the p53 function, viral proteins E1A and Apoptin utilize the p73 pathway to induce efficient tumor cell death.

Original languageEnglish
Pages (from-to)205-215
Number of pages11
JournalCell Cycle
Volume7
Issue number2
Publication statusPublished - Jan 15 2008

Keywords

  • Apoptin
  • Apoptosis
  • E1A
  • p73
  • PUMA

ASJC Scopus subject areas

  • Cell Biology
  • Biochemistry
  • Molecular Biology

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    Klanrit, P., Flinterman, M. B., Odell, E. W., Melino, G., Killick, R., Norris, J. S., & Tavassoli, M. (2008). Specific isoforms of p73 control the induction of cell death induced by the viral proteins, E1A or apoptin. Cell Cycle, 7(2), 205-215.