title: Boolean modeling identifies Greatwall/MASTL as an important regulator in the AURKA network of neuroblastoma.
abstract: Aurora Kinase A (AURKA) is often overexpressed in neuroblastoma (NB) with poor outcome. The causes of AURKA overexpression in NB are unknown. Here, we describe a gene regulatory network consisting of core regulators of AURKA protein expression and activation during mitosis to identify potential causes. This network was transformed to a dynamic Boolean model. Simulated activation of the serine/threonine protein kinase Greatwall (GWL, encoded by MASTL) that attenuates the pivotal AURKA inhibitor PP2A, predicted stabilization of AURKA. Consistent with this notion, gene set enrichment analysis showed enrichment of mitotic spindle assembly genes and MYCN target genes in NB with high GWL/MASTL expression. In line with the prediction of GWL/MASTL enhancing AURKA, elevated expression of GWL/MASTL was associated with NB risk factors and poor survival of patients. These results establish Boolean network modeling of oncogenic pathways in NB as a useful means for guided discovery in this enigmatic cancer.
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany.
authors.forename: Meike
authors.initials: M
authors.lastname: Dahlhaus
authors.affiliation: Medical Systems Biology, Ulm University, Ulm, Germany; International Graduate School of Molecular Medicine, Ulm University, Ulm, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Burkovski
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children's Hospital Cologne, Medical Faculty, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors.forename: Falk
authors.initials: F
authors.lastname: Hertwig
authors.affiliation: Medical Systems Biology, Ulm University, Ulm, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Mussel
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children's Hospital Cologne, Medical Faculty, University of Cologne, Cologne, Germany.
authors.forename: Ruth
authors.initials: R
authors.lastname: Volland
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children's Hospital Cologne, Medical Faculty, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Fischer
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany.
authors.forename: Klaus-Michael
authors.initials: KM
authors.lastname: Debatin
authors.affiliation: Medical Systems Biology, Ulm University, Ulm, Germany; Leibniz Institute on Aging, Fritz-Lipmann Institute, Jena, Germany. Electronic address: hans.kestler@uni-ulm.de.
authors.forename: Hans A
authors.initials: HA
authors.lastname: Kestler
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany. Electronic address: christian.beltinger@uniklinik-ulm.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Beltinger
mesh_terms: D000293:Adolescent; D064096:Aurora Kinase A / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D003198:Computer Simulation; D030541:Databases, Genetic; D004795:Enzyme Stability; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D008957:Models, Genetic; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000201:enzymology / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D055815:Young Adult
chemical_list: C459801:MYCN protein, human; D008869:Microtubule-Associated Proteins; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; C576917:AURKA protein, human; D064096:Aurora Kinase A; C555237:MASTL protein, human; D017346:Protein Serine-Threonine Kinases; D054648:Protein Phosphatase 2
keywords: AURKA; Boolean network; GWL/MASTL; Gene regulatory network; Neuroblastoma