Gene Network Analysis of Bone Marrow Mononuclear Cells Reveals Activation of Multiple Kinase Pathways in Human Systemic Lupus Erythematosus

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Gene Network Analysis of Bone Marrow Mononuclear Cells Reveals Activation of Multiple Kinase Pathways in Human Systemic Lupus Erythematosus

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dc.contributor.author Nakou, Magdalene
dc.contributor.author Bertsias, George
dc.contributor.author Stagakis, Ilias
dc.contributor.author Centola, Michael
dc.contributor.author Tassiulas, Ioannis
dc.contributor.author Hatziapostolou, Maria
dc.contributor.author Kritikos, Iraklis
dc.contributor.author Goulielmos, George
dc.contributor.author Boumpas, Dimitrios T.
dc.contributor.author Iliopoulos, Dimitrios
dc.date.accessioned 2011-04-27T04:07:14Z
dc.date.issued 2010
dc.identifier.citation Nakou, Magdalene, George Bertsias, Ilias Stagakis, Michael Centola, Ioannis Tassiulas, Maria Hatziapostolou, Iraklis Kritikos, George Goulielmos, Dimitrios T. Boumpas, and Dimitrios Iliopoulos. 2010. Gene Network Analysis of Bone Marrow Mononuclear Cells Reveals Activation of Multiple Kinase Pathways in Human Systemic Lupus Erythematosus. PLoS ONE 5(10): e13351. en_US
dc.identifier.issn 1932-6203 en_US
dc.identifier.uri http://nrs.harvard.edu/urn-3:HUL.InstRepos:4878084
dc.description.abstract Background: Gene profiling studies provide important information for key molecules relevant to a disease but are less informative of protein-protein interactions, post-translational modifications and regulation by targeted subcellular localization. Integration of genomic data and construction of functional gene networks may provide additional insights into complex diseases such as systemic lupus erythematosus (SLE). Methodology/Principal Findings: We analyzed gene expression microarray data of bone marrow mononuclear cells (BMMCs) from 20 SLE patients (11 with active disease) and 10 controls. Gene networks were constructed using the bioinformatic tool Ingenuity Gene Network Analysis. In SLE patients, comparative analysis of BMMCs genes revealed a network with 19 central nodes as major gene regulators including ERK, JNK, and p38 MAP kinases, insulin, Ca2+ and STAT3. Comparison between active versus inactive SLE identified 30 central nodes associated with immune response, protein synthesis, and post-transcriptional modification. A high degree of identity between networks in active SLE and non-Hodgkin's lymphoma (NHL) patients was found, with overlapping central nodes including kinases (MAPK, ERK, JNK, PKC), transcription factors (NF-kappaB, STAT3), and insulin. In validation studies, western blot analysis in splenic B cells from 5-month-old NZB/NZW F1 lupus mice showed activation of STAT3, ITGB2, HSPB1, ERK, JNK, p38, and p32 kinases, and downregulation of FOXO3 and VDR compared to normal C57Bl/6 mice. Conclusions/Significance: Gene network analysis of lupus BMMCs identified central gene regulators implicated in disease pathogenesis which could represent targets of novel therapies in human SLE. The high similarity between active SLE and NHL networks provides a molecular basis for the reported association of the former with lymphoid malignancies. en_US
dc.language.iso en_US en_US
dc.publisher Public Library of Science en_US
dc.relation.isversionof doi:10.1371/journal.pone.0013351 en_US
dc.relation.hasversion http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2954787/pdf/ en_US
dash.license LAA
dc.subject computational biology en_US
dc.subject signaling networks en_US
dc.subject immunology en_US
dc.subject autoimmunity en_US
dc.subject immune response en_US
dc.title Gene Network Analysis of Bone Marrow Mononuclear Cells Reveals Activation of Multiple Kinase Pathways in Human Systemic Lupus Erythematosus en_US
dc.type Journal Article en_US
dc.description.version Version of Record en_US
dc.relation.journal PLoS ONE en_US
dash.depositing.author Iliopoulos, Dimitrios
dc.date.available 2011-04-27T04:07:14Z
dash.affiliation.other HMS^Pathology en_US

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