p53 regulates cell survival by inhibiting PIK3CA in squamous cell carcinomas
| Autor: | Bhuvanesh Singh, Su Dao, Ivan Ngai, Pabbathi G. Reddy, Pornchai O-charoenrat, Arnold J. Levine, Christine A. Walsh, Andy Goberdhan, Pulivarthi H. Rao, Ting Chao Chou, Archontoula Stoffel |
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| Rok vydání: | 2002 |
| Předmět: |
Programmed cell death
Lung Neoplasms Cell Survival DNA Mutational Analysis Cell Down-Regulation Apoptosis Protein Serine-Threonine Kinases P110α Phosphatidylinositol 3-Kinases Catalytic Domain Proto-Oncogene Proteins Tumor Cells Cultured Genetics medicine Humans PTEN Protein kinase B PI3K/AKT/mTOR pathway Phosphoinositide-3 Kinase Inhibitors Oncogene biology Tumor Suppressor Proteins PTEN Phosphohydrolase Phosphoric Monoester Hydrolases Cell biology Gene Expression Regulation Neoplastic Protein Subunits medicine.anatomical_structure Head and Neck Neoplasms Carcinoma Squamous Cell biology.protein Cancer research Tumor Suppressor Protein p53 Signal transduction Proto-Oncogene Proteins c-akt Signal Transduction Research Paper Developmental Biology |
| Zdroj: | Genes & Development. 16:984-993 |
| ISSN: | 1549-5477 0890-9369 |
| DOI: | 10.1101/gad.973602 |
| Popis: | Interactions between the p53 and PI3K/AKTpathways play a significant role in the determination of cell death/survival. In benign cells these pathways are interrelated through the transcriptional regulation of PTEN by p53, which is required for p53-mediated apoptosis. PTEN exerts its effects by decreasing the phosphorylated AKT fraction, thereby diminishing prosurvival activities. However, the link between these pathways in cancer is not known. In this study, PIK3CA, encoding the p110α catalytic subunit of PI3K, is identified as an oncogene involved in upper aerodigestive tract (UADT) carcinomas. Simultaneous abnormalities in both pathways are rare in primary tumors, suggesting that amplification of PIK3CA and mutation ofp53 are mutually exclusive events and either event is able to promote a malignant phenotype. Moreover, the negative effect ofp53 induction on cell survival involves the transcriptional inhibition of PIK3CA that is independent of PTENactivity, as PTEN is not expressed in the primary tumors. Conversely, constitutive activation of PIK3CA results in resistance to p53-related apoptosis in PTEN deficient cells. Thus, p53 regulates cell survival by inhibiting thePI3K/AKT prosurvival signal independent of PTENin epithelial tumors. This inhibition is required for p53-mediated apoptosis in malignant cells. |
| Databáze: | OpenAIRE |
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