EPHA3
Ephrin type-A receptor 3 precursor (EC 2.7.10.1) (EPH-like kinase 4) (EK4) (hEK4) (HEK) (Human embryo kinase) (Tyrosine-protein kinase TYRO4) (Tyrosine-protein kinase receptor ETK1) (Eph-like tyrosine kinase 1) [ETK] [ETK1] [HEK] [TYRO4]
Publications[править]
Activation of a cellular senescence program is a common response to prolonged oncogene activation or tumor suppressor loss, providing a physiological mechanism for tumor suppression in premalignant cells. The link between senescence and tumor suppression supports the hypothesis that a loss-of-function screen measuring bona fide senescence marker activation should identify candidate tumor suppressors. Using a high-content siRNA screening assay for cell morphology and proliferation measures, we identify 12 senescence-regulating kinases and determine their senescence marker signatures, including elevation of senescence-associated β-galactosidase, DNA damage and p53 or p16 (INK4a) expression. Consistent with our hypothesis, SNP array CGH data supports loss of gene copy number of five senescence-suppressing genes across multiple tumor samples. One such candidate is the EPHA3 receptor tyrosine kinase, a gene commonly mutated in human cancer. We demonstrate that selected intracellular EPHA3 tumor-associated point mutations decrease receptor expression level and/or receptor tyrosine kinase (RTK) activity. Our study therefore describes a new strategy to mine for novel candidate tumor suppressors and provides compelling evidence that EPHA3 mutations may promote tumorigenesis only when key senescence-inducing pathways have been inactivated.
MeSH Terms
- Cell Line, Tumor
- Cell Transformation, Neoplastic
- Cellular Senescence
- Cyclin-Dependent Kinase Inhibitor p16
- Gene Expression Profiling
- Gene Expression Regulation, Neoplastic
- High-Throughput Screening Assays
- Humans
- Models, Molecular
- Mutation
- Oligonucleotide Array Sequence Analysis
- Polymorphism, Single Nucleotide
- RNA, Small Interfering
- Receptor Protein-Tyrosine Kinases
- Receptor, EphA3
- Signal Transduction
- Tumor Suppressor Protein p53
- beta-Galactosidase
Keywords
- DDR
- EPHA3/RTK
- p16INK4a
- p53
- senescence
- tumor suppressor