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A comprehensive assessment of networks and pathways of hypoxia-associated proteins and identification of responsive protein modules

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Abstract

The study and systematic analysis of protein–protein interaction networks relevant to disease or well-being have become an integral part of systems biology. Recent studies have revealed strong association between the topological properties and biological function of proteins in networks. Hypoxia is a pathophysiological condition which arises due to low oxygen concentration in conditions like prenatal birth, cardiovascular diseases, malignancies, inflammation, ascent to higher altitude, free diving, etc. Conventional techniques of studying a single gene or protein have not been successful in this complex disorder. Considering the complexity and multivariate nature of hypoxic stress, we aimed to identify the key proteins; the central biological regulatory pathways, and their molecular connectivity by the topological analysis of the protein–protein interaction (PPI) network. The study collected proteins whose expressions are altered in response to hypoxia, and calculated an interaction map which is termed as the giant core “hypoxia-responsive PPI network” of 603 nodes connected via 4264 edges. A backbone network of 24 bottleneck proteins with high Betweenness Centrality and large degree was identified. The robustness and accuracy of backbone network was validated by 104 test networks. The giant network was divided into five functional subnetworks, each enriched with important and distinct biological pathways. The study is the first methodological network and pathway enrichment analysis of hypoxia-regulated proteins which sheds light on the important molecular mechanisms operational during hypoxic stress. It also comprehensively describes the global protein–protein interactions, the biological subnetworks, and the backbone network regulating the hypoxic stress response. This helps to identify potential target molecules for therapy or ameliorating the pathophysiology, which could not be found merely through molecular biology methods. In principle, the methodology described may be implemented to understand the molecular mechanisms in other multivariate disorders.

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References

  • Albert R, Jeong H et al (2000) Error and attack tolerance of complex networks. Nature 406(6794):378–382

    Article  Google Scholar 

  • An SS, Pennella CM et al (2005) Hypoxia alters biophysical properties of endothelial cells via p38 MAPK- and Rho kinase-dependent pathways. Am J Physiol Cell Physiol 289(3):C521–C530

    Article  Google Scholar 

  • Arias CR, Yeh HY et al (2012) Biomarker identification for prostate cancer and lymph node metastasis from microarray data and protein interaction network using gene prioritization method. ScientificWorldJournal 2012:842727

    Article  Google Scholar 

  • Assenov Y, Ramirez F et al (2008) Computing topological parameters of biological networks. Bioinformatics 24(2):282–284

    Article  Google Scholar 

  • Bandarra D, Biddlestone J et al (2014) Hypoxia activates IKK-NF-kappaB and the immune response in Drosophila melanogaster. Biosci Rep 34(4):429–440

    Article  Google Scholar 

  • Bandyopadhyay RS, Phelan M et al (1995) Hypoxia induces AP-1-regulated genes and AP-1 transcription factor binding in human endothelial and other cell types. Biochim Biophys Acta 1264(1):72–78

    Article  Google Scholar 

  • Bashan N, Burdett E et al (1992) Regulation of glucose transport and GLUT1 glucose transporter expression by O2 in muscle cells in culture. Am J Physiol 262(3 Pt 1):C682–C690

    Google Scholar 

  • Beitner-Johnson D, Rust RT et al (2000) Regulation of CREB by moderate hypoxia in PC12 cells. Adv Exp Med Biol 475:143–152

    Article  Google Scholar 

  • Beitner-Johnson D, Rust RT et al (2001) Hypoxia activates Akt and induces phosphorylation of GSK-3 in PC12 cells. Cell Signal 13(1):23–27

    Article  Google Scholar 

  • Benita Y, Kikuchi H et al (2009) An integrative genomics approach identifies Hypoxia Inducible Factor-1 (HIF-1)-target genes that form the core response to hypoxia. Nucleic Acids Res 37(14):4587–4602

    Article  Google Scholar 

  • Bhoumik A, Lopez-Bergami P et al (2007) ATF2 on the double–activating transcription factor and DNA damage response protein. Pigment Cell Res 20(6):498–506

    Article  Google Scholar 

  • Bruick RK (2000) Expression of the gene encoding the proapoptotic Nip3 protein is induced by hypoxia. Proc Natl Acad Sci USA 97(16):9082–9087

    Article  Google Scholar 

  • Calvano SE, Xiao W et al (2005) A network-based analysis of systemic inflammation in humans. Nature 437(7061):1032–1037

    Article  Google Scholar 

  • Chen EY, Mazure NM et al (2001) Hypoxia activates a platelet-derived growth factor receptor/phosphatidylinositol 3-kinase/Akt pathway that results in glycogen synthase kinase-3 inactivation. Cancer Res 61(6):2429–2433

    Google Scholar 

  • Choi JH, Cho HK et al (2009) Activating transcription factor 2 increases transactivation and protein stability of hypoxia-inducible factor 1alpha in hepatocytes. Biochem J 424(2):285–296

    Article  MathSciNet  Google Scholar 

  • Chuang HY, Lee E et al (2007) Network-based classification of breast cancer metastasis. Mol Syst Biol 3:140

    Article  Google Scholar 

  • Conrad PW, Freeman TL et al (1999) EPAS1 trans-activation during hypoxia requires p42/p44 MAPK. J Biol Chem 274(47):33709–33713

    Article  Google Scholar 

  • Crawford JH, Isbell TS et al (2006) Hypoxia, red blood cells, and nitrite regulate NO-dependent hypoxic vasodilation. Blood 107(2):566–574

    Article  Google Scholar 

  • Croft D, Mundo AF et al (2014) The Reactome pathway knowledgebase. Nucleic Acids Res 42((Database issue)):D472–D477

    Article  Google Scholar 

  • Cummins EP, Taylor CT (2005) Hypoxia-responsive transcription factors. Pflugers Arch 450(6):363–371

    Article  Google Scholar 

  • Deng M, Zhang K et al (2003) Prediction of protein function using protein-protein interaction data. J Comput Biol 10(6):947–960

    Article  MathSciNet  Google Scholar 

  • Dittrich MT, Klau GW et al (2008) Identifying functional modules in protein-protein interaction networks: an integrated exact approach. Bioinformatics 24(13):i223–i231

    Article  Google Scholar 

  • Doncheva NT, Assenov Y et al (2012) Topological analysis and interactive visualization of biological networks and protein structures. Nat Protoc 7(4):670–685

    Article  Google Scholar 

  • Du CP, Tan R et al (2012) Fyn kinases play a critical role in neuronal apoptosis induced by oxygen and glucose deprivation or amyloid-beta peptide treatment. CNS Neurosci Ther 18(9):754–761

    Article  MathSciNet  Google Scholar 

  • Fan T, Le A et al (2014) Antagonistic effects of MYC and hypoxia in channeling glucose and glutamine into de novo nucleotide biosynthesis. Cancer Metab 2(Suppl 1):O10

    Article  Google Scholar 

  • Filippi I, Morena E et al (2014) Short-term hypoxia enhances the migratory capability of dendritic cell through HIF-1alpha and PI3 K/Akt pathway. J Cell Physiol 229(12):2067–2076

    Article  Google Scholar 

  • Flann KL, Rathbone CR et al (2014) Hypoxia simultaneously alters satellite cell-mediated angiogenesis and hepatocyte growth factor expression. J Cell Physiol 229(5):572–579

    Article  Google Scholar 

  • Franceschini A, Szklarczyk D et al (2013) STRING v9.1: protein-protein interaction networks, with increased coverage and integration. Nucleic Acids Res 41((Database issue)):D808–D815

    Article  Google Scholar 

  • Garcia-Roman J, Ibarra-Sanchez A et al (2010) VEGF secretion during hypoxia depends on free radicals-induced Fyn kinase activity in mast cells. Biochem Biophys Res Commun 401(2):262–267

    Article  Google Scholar 

  • Gardner LB, Li Q et al (2001) Hypoxia inhibits G1/S transition through regulation of p27 expression. J Biol Chem 276(11):7919–7926

    Article  Google Scholar 

  • Goehler H, Lalowski M et al (2004) A protein interaction network links GIT1, an enhancer of huntingtin aggregation, to Huntington’s disease. Mol Cell 15(6):853–865

    Article  Google Scholar 

  • Gordan JD, Thompson CB et al (2007) HIF and c-Myc: sibling rivals for control of cancer cell metabolism and proliferation. Cancer Cell 12(2):108–113

    Article  Google Scholar 

  • Graeber TG, Peterson JF et al (1994) Hypoxia induces accumulation of p53 protein, but activation of a G1-phase checkpoint by low-oxygen conditions is independent of p53 status. Mol Cell Biol 14(9):6264–6277

    Article  Google Scholar 

  • Gu YZ, Hogenesch JB et al (2000) The PAS superfamily: sensors of environmental and developmental signals. Annu Rev Pharmacol Toxicol 40:519–561

    Article  Google Scholar 

  • Gu J, Chen Y et al (2010) Identification of responsive gene modules by network-based gene clustering and extending: application to inflammation and angiogenesis. BMC Syst Biol 4:47

    Article  Google Scholar 

  • Haddad JJ, Hanbali LB (2014) Hypoxia upregulates MAPK(p38)/MAPK(ERK) phosphorylation in vitro: neuroimmunological differential time-dependent expression of MAPKs. Protein Pept Lett 21(5):444–451

    Article  Google Scholar 

  • Harding HP, Calfon M et al (2002) Transcriptional and translational control in the Mammalian unfolded protein response. Annu Rev Cell Dev Biol 18:575–599

    Article  Google Scholar 

  • Hwang T, Park T (2009) Identification of differentially expressed subnetworks based on multivariate ANOVA. BMC Bioinform 10:128

    Article  Google Scholar 

  • Ideker T, Sharan R (2008) Protein networks in disease. Genome Res 18(4):644–652

    Article  Google Scholar 

  • Jeong H, Mason SP et al (2001) Lethality and centrality in protein networks. Nature 411(6833):41–42

    Article  Google Scholar 

  • Jiang X, Zhang D et al (2015) Role of Ran-regulated nuclear-cytoplasmic trafficking of pVHL in the regulation of microtubular stability-mediated HIF-1alpha in hypoxic cardiomyocytes. Sci Rep 5:9193

    Article  Google Scholar 

  • Jonsson PF, Bates PA (2006) Global topological features of cancer proteins in the human interactome. Bioinformatics 22(18):2291–2297

    Article  Google Scholar 

  • Kaidi A, Williams AC et al (2007) Interaction between beta-catenin and HIF-1 promotes cellular adaptation to hypoxia. Nat Cell Biol 9(2):210–217

    Article  Google Scholar 

  • Kaimal V, Sardana D et al (2011) Integrative systems biology approaches to identify and prioritize disease and drug candidate genes. Methods Mol Biol 700:241–259

    Article  Google Scholar 

  • Khurana P, Sugadev R et al (2013) HypoxiaDB: a database of hypoxia-regulated proteins. Database (oxford) 2013:bat074

    Article  Google Scholar 

  • Knox R, Zhao C et al (2013) Enhanced NMDA receptor tyrosine phosphorylation and increased brain injury following neonatal hypoxia-ischemia in mice with neuronal Fyn overexpression. Neurobiol Dis 51:113–119

    Article  Google Scholar 

  • Kunz M, Moeller S et al (2003) Mechanisms of hypoxic gene regulation of angiogenesis factor Cyr61 in melanoma cells. J Biol Chem 278(46):45651–45660

    Article  Google Scholar 

  • Laderoute KR, Calaoagan JM et al (2002) The response of c-jun/AP-1 to chronic hypoxia is hypoxia-inducible factor 1 alpha dependent. Mol Cell Biol 22(8):2515–2523

    Article  Google Scholar 

  • Lam SY, Liu Y et al (2012) Chronic intermittent hypoxia induces local inflammation of the rat carotid body via functional upregulation of proinflammatory cytokine pathways. Histochem Cell Biol 137(3):303–317

    Article  Google Scholar 

  • Leonard MO, Howell K et al (2008) Hypoxia selectively activates the CREB family of transcription factors in the in vivo lung. Am J Respir Crit Care Med 178(9):977–983

    Article  Google Scholar 

  • Licht AH, Pein OT et al (2006) JunB is required for endothelial cell morphogenesis by regulating core-binding factor beta. J Cell Biol 175(6):981–991

    Article  Google Scholar 

  • Liu L, Zhang H et al (2010) ERK/MAPK activation involves hypoxia-induced MGr1-Ag/37LRP expression and contributes to apoptosis resistance in gastric cancer. Int J Cancer 127(4):820–829

    Google Scholar 

  • Maiti P, Singh SB et al (2006) Hypobaric hypoxia induces oxidative stress in rat brain. Neurochem Int 49(8):709–716

    Article  Google Scholar 

  • Majmundar AJ, Wong WJ et al (2010) Hypoxia-inducible factors and the response to hypoxic stress. Mol Cell 40(2):294–309

    Article  Google Scholar 

  • Manalo DJ, Rowan A et al (2005) Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1. Blood 105(2):659–669

    Article  Google Scholar 

  • McMurtry IF, Bauer NR et al (2003) Hypoxia and Rho/Rho-kinase signaling. Lung development versus hypoxic pulmonary hypertension. Adv Exp Med Biol 543:127–137

    Article  Google Scholar 

  • Mense SM, Sengupta A et al (2006) Gene expression profiling reveals the profound upregulation of hypoxia-responsive genes in primary human astrocytes. Physiol Genomics 25(3):435–449

    Article  Google Scholar 

  • Meyuhas R, Pikarsky E et al (2008) A Key role for cyclic AMP-responsive element binding protein in hypoxia-mediated activation of the angiogenesis factor CCN1 (CYR61) in Tumor cells. Mol Cancer Res 6(9):1397–1409

    Article  Google Scholar 

  • Murphy M, Phelps A et al (2012) Hypoxia-induced response of cell cycle and apoptosis regulators in melanoma. Int J Dermatol 51(10):1263–1267

    Article  Google Scholar 

  • Nair J, Ghatge M et al (2014) Network analysis of inflammatory genes and their transcriptional regulators in coronary artery disease. PLoS One 9(4):e94328

    Article  Google Scholar 

  • Ning W, Chu TJ et al (2004) Genome-wide analysis of the endothelial transcriptome under short-term chronic hypoxia. Physiol Genomics 18(1):70–78

    Article  Google Scholar 

  • Obacz J, Pastorekova S et al (2013) Cross-talk between HIF and p53 as mediators of molecular responses to physiological and genotoxic stresses. Mol Cancer 12(1):93

    Article  Google Scholar 

  • Oeckinghaus A, Ghosh S (2009) The NF-kappaB family of transcription factors and its regulation. Cold Spring Harb Perspect Biol 1(4):a000034

    Article  Google Scholar 

  • Orlando B, Bragazzi N et al (2013) Bioinformatics and systems biology analysis of genes network involved in OLP (Oral Lichen Planus) pathogenesis. Arch Oral Biol 58(6):664–673

    Article  Google Scholar 

  • Pore N, Jiang Z et al (2006) Akt1 activation can augment hypoxia-inducible factor-1alpha expression by increasing protein translation through a mammalian target of rapamycin-independent pathway. Mol Cancer Res 4(7):471–479

    Article  Google Scholar 

  • Premkumar DR, Adhikary G et al (2000) Intracellular pathways linking hypoxia to activation of c-fos and AP-1. Adv Exp Med Biol 475:101–109

    Article  Google Scholar 

  • Rajasekhar VK, Viale A et al (2003) Oncogenic Ras and Akt signaling contribute to glioblastoma formation by differential recruitment of existing mRNAs to polysomes. Mol Cell 12(4):889–901

    Article  Google Scholar 

  • Ran J, Li H et al (2013) Construction and analysis of the protein-protein interaction network related to essential hypertension. BMC Syst Biol 7:32

    Article  Google Scholar 

  • Romain B, Hachet-Haas M et al (2014) Hypoxia differentially regulated CXCR4 and CXCR7 signaling in colon cancer. Mol Cancer 13:58

    Article  Google Scholar 

  • Rosenwald IB, Setkov NA et al (1995) Transient inhibition of protein synthesis induces expression of proto-oncogenes and stimulates resting cells to enter the cell cycle. Cell Prolif 28(12):631–644

    Article  Google Scholar 

  • Salnikow K, Kluz T et al (2002) The regulation of hypoxic genes by calcium involves c-Jun/AP-1, which cooperates with hypoxia-inducible factor 1 in response to hypoxia. Mol Cell Biol 22(6):1734–1741

    Article  Google Scholar 

  • Salnikow K, Davidson T et al (2003) The involvement of hypoxia-inducible transcription factor-1-dependent pathway in nickel carcinogenesis. Cancer Res 63(13):3524–3530

    Google Scholar 

  • Sarada S, Himadri P et al (2008) Role of oxidative stress and NFkB in hypoxia-induced pulmonary edema. Exp Biol Med (Maywood) 233(9):1088–1098

    Article  Google Scholar 

  • Sarajlic A, Janjic V et al (2013) Network topology reveals key cardiovascular disease genes. PLoS One 8(8):e71537

    Article  Google Scholar 

  • Schioppa T, Uranchimeg B et al (2003) Regulation of the chemokine receptor CXCR4 by hypoxia. J Exp Med 198(9):1391–1402

    Article  Google Scholar 

  • Schweppe RE, Cheung TH et al (2006) Global gene expression analysis of ERK5 and ERK1/2 signaling reveals a role for HIF-1 in ERK5-mediated responses. J Biol Chem 281(30):20993–21003

    Article  Google Scholar 

  • Semenza GL (1998) Hypoxia-inducible factor 1: master regulator of O2 homeostasis. Curr Opin Genet Dev 8(5):588–594

    Article  Google Scholar 

  • Semenza GL (2000) HIF-1 and human disease: one highly involved factor. Genes Dev 14(16):1983–1991

    Google Scholar 

  • Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3(10):721–732

    Article  Google Scholar 

  • Semenza GL (2011) Hypoxia. Cross talk between oxygen sensing and the cell cycle machinery. Am J Physiol Cell Physiol 301(3):C550–C552

    Article  Google Scholar 

  • Sermeus A, Michiels C (2011) Reciprocal influence of the p53 and the hypoxic pathways. Cell Death Dis 2:e164

    Article  Google Scholar 

  • Sethy NK, Singh M et al (2011) Upregulation of transcription factor NRF2-mediated oxidative stress response pathway in rat brain under short-term chronic hypobaric hypoxia. Funct Integr Genomics 11(1):119–137

    Article  Google Scholar 

  • Shah YM, Xie L (2014) Hypoxia-inducible factors link iron homeostasis and erythropoiesis. Gastroenterology 146(3):630–642

    Article  Google Scholar 

  • Shannon P, Markiel A et al (2003) Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 13(11):2498–2504

    Article  Google Scholar 

  • Sheets MD, Fox CA et al (1994) The 3′-untranslated regions of c-mos and cyclin mRNAs stimulate translation by regulating cytoplasmic polyadenylation. Genes Dev 8(8):926–938

    Article  Google Scholar 

  • Shin J, Lee HJ et al (2011) Suppression of STAT3 and HIF-1 alpha mediates anti-angiogenic activity of betulinic acid in hypoxic PC-3 prostate cancer cells. PLoS One 6(6):e21492

    Article  MathSciNet  Google Scholar 

  • Sonna LA, Cullivan ML et al (2003) Effect of hypoxia on gene expression by human hepatocytes (HepG2). Physiol Genomics 12(3):195–207

    Article  Google Scholar 

  • Toschi A, Lee E et al (2008) Differential dependence of hypoxia-inducible factors 1 alpha and 2 alpha on mTORC1 and mTORC2. J Biol Chem 283(50):34495–34499

    Article  Google Scholar 

  • Tsai YP, Wu KJ (2012) Hypoxia-regulated target genes implicated in tumor metastasis. J Biomed Sci 19:102

    Article  Google Scholar 

  • Vengellur A, Woods BG et al (2003) Gene expression profiling of the hypoxia signaling pathway in hypoxia-inducible factor 1alpha null mouse embryonic fibroblasts. Gene Expr 11(3–4):181–197

    Article  Google Scholar 

  • Vengellur A, Phillips JM et al (2005) Gene expression profiling of hypoxia signaling in human hepatocellular carcinoma cells. Physiol Genomics 22(3):308–318

    Article  Google Scholar 

  • Villar D, Ortiz-Barahona A et al (2012) Cooperativity of stress-responsive transcription factors in core hypoxia-inducible factor binding regions. PLoS One 7(9):e45708

    Article  Google Scholar 

  • Wang V, Davis DA et al (2005) Differential gene up-regulation by hypoxia-inducible factor-1alpha and hypoxia-inducible factor-2alpha in HEK293T cells. Cancer Res 65(8):3299–3306

    Google Scholar 

  • Wang Q, Donthi RV et al (2008) Cardiac phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase increases glycolysis, hypertrophy, and myocyte resistance to hypoxia. Am J Physiol Heart Circ Physiol 294(6):H2889–H2897

    Article  Google Scholar 

  • Wenger RH (2002) Cellular adaptation to hypoxia: O2-sensing protein hydroxylases, hypoxia-inducible transcription factors, and O2-regulated gene expression. FASEB J 16(10):1151–1162

    Article  Google Scholar 

  • Wierenga AT, Vellenga E et al (2014) Convergence of hypoxia and TGFbeta pathways on cell cycle regulation in human hematopoietic stem/progenitor cells. PLoS One 9(3):e93494

    Article  Google Scholar 

  • Wu G, Feng X et al (2010) A human functional protein interaction network and its application to cancer data analysis. Genome Biol 11(5):R53

    Article  Google Scholar 

  • Yokogami K, Yamashita S et al (2013) Hypoxia-induced decreases in SOCS3 increase STAT3 activation and upregulate VEGF gene expression. Brain Tumor Pathol 30(3):135–143

    Article  Google Scholar 

  • Yu H, Kim PM et al (2007) The importance of bottlenecks in protein networks: correlation with gene essentiality and expression dynamics. PLoS Comput Biol 3(4):e59

    Article  MathSciNet  Google Scholar 

  • Yuan G, Adhikary G et al (2004) Role of oxidative stress in intermittent hypoxia-induced immediate early gene activation in rat PC12 cells. J Physiol 557(Pt 3):773–783

    Article  Google Scholar 

  • Zhang W, Liu HT (2002) MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Res 12(1):9–18

    Article  Google Scholar 

  • Zhang H, Akman HO et al (2003) Cellular response to hypoxia involves signaling via Smad proteins. Blood 101(6):2253–2260

    Article  Google Scholar 

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Acknowledgments

The authors are thankful to Ms. Mitali Kaushik, Jamia Milia Islamia for the help in the preparation of figures.

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  1. Bioinformatics Group, Defence Institute of Physiology and Allied Sciences (DIPAS), Defence R&D Organization, Ministry of Defence, Lucknow Road, Timarpur, New Delhi, 110054, India

    Pankaj Khurana, Divya Tiwari, R. Sugadev, Soma Sarkar & Shashi Bala Singh

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  1. Pankaj Khurana
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  2. Divya Tiwari
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Correspondence to Pankaj Khurana.

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Khurana, P., Tiwari, D., Sugadev, R. et al. A comprehensive assessment of networks and pathways of hypoxia-associated proteins and identification of responsive protein modules. Netw Model Anal Health Inform Bioinforma 5, 17 (2016). https://doi.org/10.1007/s13721-016-0123-8

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