The study investigates the role of p53-dependent cellular senescence in suppressing Pten-deficient tumorigenesis. Key findings include: 1. **Cellular Senescence and Tumorigenesis**: Cellular senescence, a form of permanent cell cycle arrest, is shown to be crucial in restricting tumorigenesis in vivo. In mice, conditional inactivation of Trp53 (p53) in the prostate does not lead to tumor formation, while complete Pten inactivation triggers non-lethal invasive prostate cancer after a long latency period. 2. ** combined Inactivation**: Combined inactivation of Pten and Trp53 results in early and lethal invasive prostate cancer, with all mice dying by 7 months of age. 3. **Molecular Mechanisms**: Acute loss of Pten induces growth arrest through the p53-dependent cellular senescence pathway, which can be rescued by combined loss of Trp53. This pathway involves upregulation of p19Arf and p21, leading to p53 stabilization and senescence induction. 4. **In Vivo Evidence**: Evidence of cellular senescence is detected in early-stage human prostate cancer specimens, supporting the relevance of this pathway in vivo. 5. **Therapeutic Implications**: The findings suggest that PTEN-deficient prostate cancer might benefit from treatments that potentiate p53 activation or stabilize WT p53, potentially through mechanisms that induce cellular senescence. 6. **Model for Tumour Suppression**: A model is proposed where p53 acts as a failsafe protein in Pten-deficient tumours, and the cooperative tumour suppression involves both genes working together to prevent tumour progression. These results highlight the importance of cellular senescence in tumour suppression and provide insights into the molecular relationship between Pten and p53 in prostate cancer.The study investigates the role of p53-dependent cellular senescence in suppressing Pten-deficient tumorigenesis. Key findings include: 1. **Cellular Senescence and Tumorigenesis**: Cellular senescence, a form of permanent cell cycle arrest, is shown to be crucial in restricting tumorigenesis in vivo. In mice, conditional inactivation of Trp53 (p53) in the prostate does not lead to tumor formation, while complete Pten inactivation triggers non-lethal invasive prostate cancer after a long latency period. 2. ** combined Inactivation**: Combined inactivation of Pten and Trp53 results in early and lethal invasive prostate cancer, with all mice dying by 7 months of age. 3. **Molecular Mechanisms**: Acute loss of Pten induces growth arrest through the p53-dependent cellular senescence pathway, which can be rescued by combined loss of Trp53. This pathway involves upregulation of p19Arf and p21, leading to p53 stabilization and senescence induction. 4. **In Vivo Evidence**: Evidence of cellular senescence is detected in early-stage human prostate cancer specimens, supporting the relevance of this pathway in vivo. 5. **Therapeutic Implications**: The findings suggest that PTEN-deficient prostate cancer might benefit from treatments that potentiate p53 activation or stabilize WT p53, potentially through mechanisms that induce cellular senescence. 6. **Model for Tumour Suppression**: A model is proposed where p53 acts as a failsafe protein in Pten-deficient tumours, and the cooperative tumour suppression involves both genes working together to prevent tumour progression. These results highlight the importance of cellular senescence in tumour suppression and provide insights into the molecular relationship between Pten and p53 in prostate cancer.