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

Apoptin, a protein derived from the chicken anaemia virus, induces cell death in various cancer cells but shows little or no cytotoxicity in normal cells. The mechanism of apoptin-induced cell death is currently unknown but it appears to induce apoptosis independent of p53 status. Here we show that...

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Bibliographic Details
Published in:Apoptosis (London) 2012-08, Vol.17 (8), p.762-776
Main Authors: Taebunpakul, P., Sayan, B. S., Flinterman, M., Klanrit, P., Gäken, J., Odell, E. W., Melino, G., Tavassoli, M.
Format: Article
Language:English
Subjects:
Apoptosis
Apoptosis Regulatory Proteins - genetics
Apoptosis Regulatory Proteins - metabolism
Biochemistry
Biomedical and Life Sciences
Biomedicine
Cancer Research
Capsid Proteins - biosynthesis
Capsid Proteins - physiology
Cell Biology
Cell Line, Tumor
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
G2 Phase Cell Cycle Checkpoints
Half-Life
Humans
Nuclear Proteins - genetics
Nuclear Proteins - metabolism
Oncology
Original Paper
Poly (ADP-Ribose) Polymerase-1
Poly(ADP-ribose) Polymerases - metabolism
Protein Isoforms - metabolism
Protein Processing, Post-Translational
Protein Stability
Proteolysis
Proto-Oncogene Proteins - genetics
Proto-Oncogene Proteins - metabolism
Tumor Protein p73
Tumor Suppressor Protein p53 - metabolism
Tumor Suppressor Proteins - genetics
Tumor Suppressor Proteins - metabolism
Ubiquitin-Protein Ligases - metabolism
Ubiquitination
Virology
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Summary:Apoptin, a protein derived from the chicken anaemia virus, induces cell death in various cancer cells but shows little or no cytotoxicity in normal cells. The mechanism of apoptin-induced cell death is currently unknown but it appears to induce apoptosis independent of p53 status. Here we show that p73, a p53 family member, is important in apoptin-induced apoptosis. In p53 deficient and/or mutated cells, apoptin induced the expression of TAp73 leading to the induction of apoptosis. Knockdown of p73 using siRNA resulted in a significant reduction in apoptin-induced cytotoxicity. The p53 and p73 pro-apoptotic target PUMA plays an important role in apoptin-induced cell death as knockdown of PUMA significantly reduced cell sensitivity to apoptin. Importantly, apoptin expression resulted in a marked increase in TAp73 protein stability. Investigation into the mechanisms of TAp73 stability showed that apoptin induced the expression of the ring finger domain ubiquitin ligase PIR2 which is involved in the degradation of the anti-apoptotic ∆Np73 isoform. Collectively, our results suggest a novel mechanism of apoptin-induced apoptosis through increased TAp73 stability and induction of PIR2 resulting in the degradation of ∆Np73 and activation of pro-apoptotic targets such as PUMA causing cancer cell death.
ISSN:1360-8185
1573-675X
DOI:10.1007/s10495-012-0720-7