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Cell Cycle. 2013 Feb 15;12(4):625-34. doi: 10.4161/cc.23515. Epub 2013 Jan 16.

A high-content cellular senescence screen identifies candidate tumor suppressors, including EPHA3.

Author information

1
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.

Abstract

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.

KEYWORDS:

DDR; EPHA3/RTK; p16INK4a; p53; senescence; tumor suppressor

PMID:
23324396
PMCID:
PMC3594263
DOI:
10.4161/cc.23515
[Indexed for MEDLINE]
Free PMC Article
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