title: Integrated analysis of ATM mediated gene and protein expression impacting cellular metabolism.
abstract: A major goal of systems biology is to decipher cellular responses to genetic perturbations or environmental changes. Network integration of high-throughput data sets such as transcriptomics, proteomics, and metabolomics ("3-omics") offers a powerful tool for understanding the regulation and organization of cellular functions and biological processes. Given that the ATM (the product of the ataxia-telangiectasia mutated) gene exhibits multifaceted functions involved in complex biological networks, we attempted to analyze "3-omics" data sets by utilizing a functional pathway analysis approach. ATM-mediated gene and protein expression and metabolite products were interrogated using a model system comprised of cells genetically similar but demonstrating ATM deficiency (AT5BIVA) or ATM proficiency (ATCL8). Here, we report an unprecedented finding from the results of this integrated analysis revealing that ATM dictates purine, pyrimidine, and urea cycle pathways through the regulation of adenosine monophosphate (AMP) activated protein kinase (AMPK), a major sensor and regulator of cellular energy homeostasis. Furthermore, our results support the feasibility of applying a systems approach for identification of specific cellular networks and understanding of pathway perturbations underlying the complex A-T clinical syndrome.
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center at Georgetown University Medical Center, Washington, DC 20057, United States. akc27@georgetown.edu
authors.forename: Amrita K
authors.initials: AK
authors.lastname: Cheema
authors.forename: Olga
authors.initials: O
authors.lastname: Timofeeva
authors.forename: Rency
authors.initials: R
authors.lastname: Varghese
authors.forename: Alexandre
authors.initials: A
authors.lastname: Dimtchev
authors.forename: Kathryn
authors.initials: K
authors.lastname: Shiekh
authors.forename: Vladimir
authors.initials: V
authors.lastname: Shulaev
authors.forename: Simeng
authors.initials: S
authors.lastname: Suy
authors.forename: Sean
authors.initials: S
authors.lastname: Collins
authors.forename: Habtom
authors.initials: H
authors.lastname: Ressom
authors.forename: Mira
authors.initials: M
authors.lastname: Jung
authors.forename: Anatoly
authors.initials: A
authors.lastname: Dritschilo
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000249:Adenosine Monophosphate / Q000378:metabolism; D064007:Ataxia Telangiectasia Mutated Proteins; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology; D002853:Chromatography, Liquid; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015180:Electrophoresis, Gel, Two-Dimensional; D004734:Energy Metabolism / Q000502:physiology*; D020869:Gene Expression Profiling / Q000379:methods; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics / Q000502:physiology*; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D013058:Mass Spectrometry; D055432:Metabolomics / Q000379:methods; D046228:Microarray Analysis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D040901:Proteomics / Q000379:methods; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D049490:Systems Biology / Q000379:methods*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D000249:Adenosine Monophosphate; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases