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Functional proteomics analysis to study ATM dependent signaling in response to ionizing radiation
Amrita K Cheema1,2, Rency S Varghese1, Olga Timofeeva1
1Department of Oncology, Georgetown University Medical Center, Washington, DC.
Abstract:
Ataxia telangiectasia (AT) is a human genetic disease characterized by radiation sensitivity, impaired neuronal development and predisposition to cancer. Using a genetically defined model cell system consisting of cells expressing a kinase dead or a kinase proficient ATM gene product, we previously reported systemic alterations in major metabolic pathways that translate at the gene expression, protein and small molecule metabolite levels. Here, we report ionizing radiation induced stress response signaling arising from perturbations in the ATM gene, by employing a functional proteomics approach. Functional pathway analysis shows robust translational and post-translational responses under ATM proficient conditions, which include enrichment of proteins in the Ephrin receptor and axonal guidance signaling pathways. These molecular networks offer a hypothesis generating function for further investigations of cellular stress responses.
Insights
Ataxia telangiectasia (AT) is a genetic disorder. This study reveals how ATM gene perturbations trigger stress responses, impacting cellular pathways like axonal guidance, crucial for understanding AT disease mechanisms.
Area of Science:
- Genetics
- Molecular Biology
- Cellular Biology
Background:
- Ataxia telangiectasia (AT) is a severe human genetic disorder.
- AT is characterized by radiation sensitivity, impaired neuronal development, and cancer predisposition.
- Previous research identified metabolic pathway alterations in AT models.
Purpose of the Study:
- To investigate ionizing radiation-induced stress response signaling in ATM gene perturbations.
- To elucidate the role of the ATM gene in cellular stress response pathways.
Main Methods:
- Utilized a genetically defined model cell system with kinase-dead or kinase-proficient ATM.
- Employed a functional proteomics approach to analyze protein expression and modifications.
- Conducted functional pathway analysis on the proteomic data.
Main Results:
- Identified robust translational and post-translational responses under ATM-proficient conditions.
- Observed enrichment of proteins in Ephrin receptor and axonal guidance signaling pathways.
- Demonstrated ATM gene perturbations trigger specific stress response signaling cascades.
Conclusions:
- ATM gene perturbations significantly influence cellular stress responses.
- Ephrin receptor and axonal guidance pathways are implicated in ATM-mediated cellular stress.
- These findings provide a basis for further research into AT cellular mechanisms and potential therapeutic targets.
