Apoptin induces apoptosis by changing the equilibrium between the stability of TAp73 and ΔNp73 isoforms through ubiquitin ligase PIR2
Copyright policy )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 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.
- Cornell University United States
- King's College London United Kingdom
- University of Rome Tor Vergata Italy
- University of Salford United Kingdom
- University of Southampton United Kingdom
Ubiquitin ligase E3, Ubiquitin-Protein Ligase, TUMOR-CELLS, Poly (ADP-Ribose) Polymerase-1, Apoptosis, CHICKEN ANEMIA VIRUS, Protein Isoforms, Proteolysi, Poly(ADP-ribose) Polymerase, REGULATES P73, Nuclear Protein, Proto-Oncogene Protein, Settore BIO/11 - BIOLOGIA MOLECOLARE, Apoptosis Regulatory Protein, Tumor, Proteolysis; Ubiquitin-Protein Ligases; Tumor Suppressor Protein p53; Apoptosis; Capsid Proteins; G2 Phase Cell Cycle Checkpoints; DNA-Binding Proteins; Humans; Protein Stability; Protein Processing, Post-Translational; Apoptosis Regulatory Proteins; Cell Line, Tumor; Protein Isoforms; Tumor Suppressor Proteins; Proto-Oncogene Proteins; Half-Life; Nuclear Proteins; Poly(ADP-ribose) Polymerases; Ubiquitination, NUCLEAR ACCUMULATION, Protein Stability, INDUCTION, G2 Phase Cell Cycle Checkpoint, P73, Nuclear Proteins, Capsid Protein, DNA-Binding Proteins, G2 Phase Cell Cycle Checkpoints, Poly(ADP-ribose) Polymerases, PROTEIN STABILITY, Human, Half-Life, 570, DNA-Binding Protein, Ubiquitin-Protein Ligases, p73, 610, RNF144B, Cell Line, PIR2, PUMA, Cell Line, Tumor, Proto-Oncogene Proteins, Humans, CANCER-CELLS, Protein Processing, P53, Tumor Suppressor Protein, Tumor Suppressor Proteins, Post-Translational, Ubiquitination, Apoptosi, Protein Isoform, Tumor Protein p73, DNA-DAMAGE, Apoptin, Proteolysis, Capsid Proteins, Tumor Suppressor Protein p53, Apoptosis Regulatory Proteins, Protein Processing, Post-Translational
Ubiquitin ligase E3, Ubiquitin-Protein Ligase, TUMOR-CELLS, Poly (ADP-Ribose) Polymerase-1, Apoptosis, CHICKEN ANEMIA VIRUS, Protein Isoforms, Proteolysi, Poly(ADP-ribose) Polymerase, REGULATES P73, Nuclear Protein, Proto-Oncogene Protein, Settore BIO/11 - BIOLOGIA MOLECOLARE, Apoptosis Regulatory Protein, Tumor, Proteolysis; Ubiquitin-Protein Ligases; Tumor Suppressor Protein p53; Apoptosis; Capsid Proteins; G2 Phase Cell Cycle Checkpoints; DNA-Binding Proteins; Humans; Protein Stability; Protein Processing, Post-Translational; Apoptosis Regulatory Proteins; Cell Line, Tumor; Protein Isoforms; Tumor Suppressor Proteins; Proto-Oncogene Proteins; Half-Life; Nuclear Proteins; Poly(ADP-ribose) Polymerases; Ubiquitination, NUCLEAR ACCUMULATION, Protein Stability, INDUCTION, G2 Phase Cell Cycle Checkpoint, P73, Nuclear Proteins, Capsid Protein, DNA-Binding Proteins, G2 Phase Cell Cycle Checkpoints, Poly(ADP-ribose) Polymerases, PROTEIN STABILITY, Human, Half-Life, 570, DNA-Binding Protein, Ubiquitin-Protein Ligases, p73, 610, RNF144B, Cell Line, PIR2, PUMA, Cell Line, Tumor, Proto-Oncogene Proteins, Humans, CANCER-CELLS, Protein Processing, P53, Tumor Suppressor Protein, Tumor Suppressor Proteins, Post-Translational, Ubiquitination, Apoptosi, Protein Isoform, Tumor Protein p73, DNA-DAMAGE, Apoptin, Proteolysis, Capsid Proteins, Tumor Suppressor Protein p53, Apoptosis Regulatory Proteins, Protein Processing, Post-Translational
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