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

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.

TAp73 knockout shows genomic instability with infertility and tumor suppressor functions

“…Over the last few years, several studies have suggested specific roles for particular p73 isoforms (De Laurenzi et al 1998;Murray-Zmijewski et al 2006;Klanrit et al 2008). Thus, these data indicate that the ratio of various p73 isoforms present in an individual cell determines the outcome of p73 function, rather than the sum of the activities of each isolated p73 isoform.…”

Apoptin induces apoptosis by changing the equilibrium between the stability of TAp73 and ΔNp73 isoforms through ubiquitin ligase PIR2

“…Interaction of certain viral proteins with key cellular components such as p53 and pRB causes deregulation of the cell cycle program and consequently cellular transformation. Additionally, there is clear evidence for the role of viruses, through the specific function of viral proteins such as E1A of human adenovirus, in the induction of tumour specific cell death [43,50,51]. The potential use of viruses and viral derived proteins in cancer therapy is of major interest at present.…”

“…Additionally, we have recently shown that apoptin induces the expression of the p53/p73 pro-apoptotic target PUMA [43]. To further investigate the importance of PUMA in apoptin-induced apoptosis, PUMA knockout HCT116 cells were investigated.…”

“…We have previously shown that apoptin has no effect on the transactivation of p73 isoforms [43]. We therefore investigated the effect of apoptin on the protein stability of TAp73a and DNp73a isoforms using p73 isoform specific inducible Saos-2 cells.…”

“…Similar to p53, p73 can transactivate PUMA by binding to the same p53-responsive element in the PUMA promoter in response to DNA damage [41,42]. We have recently shown that apoptin expression induces the endogenous protein levels of TAp73 in p53-mutated head and neck squamous cell carcinoma H357 suggesting an important role for p73 in the regulation of apoptin-induced apoptosis [43]. However, the mechanism by which apoptin activates TAp73 remained unknown.…”