Mutant p53-R273H mediates cancer cell survival and anoikis resistance through AKT-dependent suppression of BCL2-modifying factor (BMF)
| Autor: | C-O Leong, Heng Lungh Choo, Shew Fung Wong, L-W Hii, K H Tiong, Felicia Fei-Lei Chung, N Tw Khor, Boon Shing Tan, Rozita Rosli, I Ks Yap, S-K Cheong, Si Hoey Tan, S Pani |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Cancer Research
Carcinogenesis Cell Survival Immunology Mutant Mutation Missense Apoptosis Biology medicine.disease_cause Cellular and Molecular Neuroscience Phosphatidylinositol 3-Kinases Neoplasms medicine Gene silencing Humans Anoikis Protein kinase B PI3K/AKT/mTOR pathway Adaptor Proteins Signal Transducing Cell Biology Cell biology Gene Expression Regulation Neoplastic Oncogene Protein v-akt Proto-Oncogene Proteins c-bcl-2 Drug Resistance Neoplasm Cancer cell MCF-7 Cells Original Article Signal transduction Tumor Suppressor Protein p53 Signal Transduction |
| Zdroj: | Cell Death & Disease |
| ISSN: | 2041-4889 |
| Popis: | p53 is the most frequently mutated tumor-suppressor gene in human cancers. Unlike other tumor-suppressor genes, p53 mutations mainly occur as missense mutations within the DNA-binding domain, leading to the expression of full-length mutant p53 protein. Mutant p53 proteins not only lose their tumor-suppressor function, but may also gain new oncogenic functions and promote tumorigenesis. Here, we showed that silencing of endogenous p53-R273H contact mutant, but not p53-R175H conformational mutant, reduced AKT phosphorylation, induced BCL2-modifying factor (BMF) expression, sensitized BIM dissociation from BCL-XL and induced mitochondria-dependent apoptosis in cancer cells. Importantly, cancer cells harboring endogenous p53-R273H mutant were also found to be inherently resistant to anoikis and lack BMF induction following culture in suspension. Underlying these activities is the ability of p53-R273H mutant to suppress BMF expression that is dependent on constitutively active PI3K/AKT signaling. Collectively, these findings suggest that p53-R273H can specifically drive AKT signaling and suppress BMF expression, resulting in enhanced cell survivability and anoikis resistance. These findings open the possibility that blocking of PI3K/AKT will have therapeutic benefit in mutant p53-R273H expressing cancers. |
| Databáze: | OpenAIRE |
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