title: Characterization of p38 MAPK isoforms for drug resistance study using systems biology approach.
abstract: BACKGROUND
  p38 mitogen-activated protein kinase activation plays an important role in resistance to chemotherapeutic cytotoxic drugs in treating multiple myeloma (MM). However, how the p38 mitogen-activated protein kinase signaling pathway is involved in drug resistance, in particular the roles that the various p38 isoforms play, remains largely unknown.
  
  
  METHODS
  To explore the underlying mechanisms, we developed a novel systems biology approach by integrating liquid chromatography-mass spectrometry and reverse phase protein array data from human MM cell lines with computational pathway models in which the unknown parameters were inferred using a proposed novel algorithm called modularized factor graph.
  
  
  RESULTS
  New mechanisms predicted by our models suggest that combined activation of various p38 isoforms may result in drug resistance in MM via regulating the related pathways including extracellular signal-regulated kinase (ERK) pathway and NFкB pathway. ERK pathway regulating cell growth is synergistically regulated by p38δ isoform, whereas nuclear factor kappa B (NFкB) pathway regulating cell apoptosis is synergistically regulated by p38α isoform. This finding that p38δ isoform promotes the phosphorylation of ERK1/2 in MM cells treated with bortezomib was validated by western blotting. Based on the predicted mechanisms, we further screened drug combinations in silico and found that a promising drug combination targeting ERK1/2 and NFκB might reduce the effects of drug resistance in MM cells. This study provides a framework of a systems biology approach to studying drug resistance and drug combination selection.
  
  
  METHODS
  RPPA experimental Data and Matlab source codes of modularized factor graph for parameter estimation are freely available online at http://ctsb.is.wfubmc.edu/publications/modularized-factor-graph.php.
authors.affiliation: Center for Bioinformatics & Systems Biology and Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA, Department of Radiology, The Methodist Hospital Research Institute, Houston, TX 77030, USA, Department of Pathology, The Methodist Hospital Research Institute, Houston, TX 77030, USA, Proteomics Programmatic Core Laboratory, The Methodist Hospital Research Institute, Houston, TX 77030, USA, College of Computer and Information Science, Southwest University, Chongqing 400715, China, Department of Pathology, Florida Hospital, Orlando, FL 32803, USA.
authors.forename: Huiming
authors.initials: H
authors.lastname: Peng
authors.affiliation: Center for Bioinformatics & Systems Biology and Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA, Department of Radiology, The Methodist Hospital Research Institute, Houston, TX 77030, USA, Department of Pathology, The Methodist Hospital Research Institute, Houston, TX 77030, USA, Proteomics Programmatic Core Laboratory, The Methodist Hospital Research Institute, Houston, TX 77030, USA, College of Computer and Information Science, Southwest University, Chongqing 400715, China, Department of Pathology, Florida Hospital, Orlando, FL 32803, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Peng
authors.affiliation: Center for Bioinformatics & Systems Biology and Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA, Department of Radiology, The Methodist Hospital Research Institute, Houston, TX 77030, USA, Department of Pathology, The Methodist Hospital Research Institute, Houston, TX 77030, USA, Proteomics Programmatic Core Laboratory, The Methodist Hospital Research Institute, Houston, TX 77030, USA, College of Computer and Information Science, Southwest University, Chongqing 400715, China, Department of Pathology, Florida Hospital, Orlando, FL 32803, USA.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Wen
authors.affiliation: Center for Bioinformatics & Systems Biology and Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA, Department of Radiology, The Methodist Hospital Research Institute, Houston, TX 77030, USA, Department of Pathology, The Methodist Hospital Research Institute, Houston, TX 77030, USA, Proteomics Programmatic Core Laboratory, The Methodist Hospital Research Institute, Houston, TX 77030, USA, College of Computer and Information Science, Southwest University, Chongqing 400715, China, Department of Pathology, Florida Hospital, Orlando, FL 32803, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Engler
authors.affiliation: Center for Bioinformatics & Systems Biology and Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA, Department of Radiology, The Methodist Hospital Research Institute, Houston, TX 77030, USA, Department of Pathology, The Methodist Hospital Research Institute, Houston, TX 77030, USA, Proteomics Programmatic Core Laboratory, The Methodist Hospital Research Institute, Houston, TX 77030, USA, College of Computer and Information Science, Southwest University, Chongqing 400715, China, Department of Pathology, Florida Hospital, Orlando, FL 32803, USA.
authors.forename: Risë K
authors.initials: RK
authors.lastname: Matsunami
authors.affiliation: Center for Bioinformatics & Systems Biology and Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA, Department of Radiology, The Methodist Hospital Research Institute, Houston, TX 77030, USA, Department of Pathology, The Methodist Hospital Research Institute, Houston, TX 77030, USA, Proteomics Programmatic Core Laboratory, The Methodist Hospital Research Institute, Houston, TX 77030, USA, College of Computer and Information Science, Southwest University, Chongqing 400715, China, Department of Pathology, Florida Hospital, Orlando, FL 32803, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Su
authors.affiliation: Center for Bioinformatics & Systems Biology and Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA, Department of Radiology, The Methodist Hospital Research Institute, Houston, TX 77030, USA, Department of Pathology, The Methodist Hospital Research Institute, Houston, TX 77030, USA, Proteomics Programmatic Core Laboratory, The Methodist Hospital Research Institute, Houston, TX 77030, USA, College of Computer and Information Science, Southwest University, Chongqing 400715, China, Department of Pathology, Florida Hospital, Orlando, FL 32803, USA.
authors.forename: Le
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Center for Bioinformatics & Systems Biology and Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA, Department of Radiology, The Methodist Hospital Research Institute, Houston, TX 77030, USA, Department of Pathology, The Methodist Hospital Research Institute, Houston, TX 77030, USA, Proteomics Programmatic Core Laboratory, The Methodist Hospital Research Institute, Houston, TX 77030, USA, College of Computer and Information Science, Southwest University, Chongqing 400715, China, Department of Pathology, Florida Hospital, Orlando, FL 32803, USA.
authors.forename: Chung-Che Jeff
authors.initials: CC
authors.lastname: Chang
authors.affiliation: Center for Bioinformatics & Systems Biology and Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA, Department of Radiology, The Methodist Hospital Research Institute, Houston, TX 77030, USA, Department of Pathology, The Methodist Hospital Research Institute, Houston, TX 77030, USA, Proteomics Programmatic Core Laboratory, The Methodist Hospital Research Institute, Houston, TX 77030, USA, College of Computer and Information Science, Southwest University, Chongqing 400715, China, Department of Pathology, Florida Hospital, Orlando, FL 32803, USACenter for Bioinformatics & Systems Biology and Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA, Department of Radiology, The Methodist Hospital Research Institute, Houston, TX 77030, USA, Department of Pathology, The Methodist Hospital Research Institute, Houston, TX 77030, USA, Proteomics Programmatic Core Laboratory, The Methodist Hospital Research Institute, Houston, TX 77030, USA, College of Computer and Information Science, Southwest University, Chongqing 400715, China, Department of Pathology, Florida Hospital, Orlando, FL 32803, USA.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Zhou
mesh_terms: D002460:Cell Line; D049109:Cell Proliferation; D004351:Drug Resistance; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects; D049490:Systems Biology / Q000379:methods; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D007527:Isoenzymes; D016328:NF-kappa B; D048051:p38 Mitogen-Activated Protein Kinases