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Supplementary Table 2: Description of the gene pathways significantly altered in figures 13 and 14. 1. Muscle_Myosin 2. GLUCO 3. Glycolysis_and_Gluconeogenesis 4. Bile_acid_biosynthesis 5. ROS 6. Cdc25 7. GlycolysisPathway 8. Nos1 9. Eif2 10. FOSB 11. Mef2d 12. Ndk_Dynamin 13. Androgen_genes 14. Peng_GLUT_UP 15. Glycolysis 16. Glycogen_Metabolism 17. Peng_Leucine_UP 18. Carbon_Fixation 19. ST_Interferon_Gamma 20. ST_Type_I_Interferon 21. TCA Genes related to muscle myosin Genes involved in glucose processing Genes involved in glycolysis and gluconeogenesis Genes involved in bile acid biosynthesis Reactive oxidative species related genes The protein phosphatase Cdc25 is phosphorylated by Chk1 and activates Cdc2 to stimulate eukaryotic cells into M phase. Glycolysis is an evolutionarily conserved pathway by which one glucose molecule is converted to two pyruvate molecules for a gain of 2 ATP. Glutamate stimulates NMDA-mediated calcium influx, which promotes nitric oxide synthesis from arginine by neuronal nitric oxide synthase, activating guanylate cyclase. Eukaryotic initiation factor 2 (EIF2) initiates translation by transferring Met-tRNA to the 40S ribosome in a GTP-dependent process. FOSB gene expression and drug abuse Mef2 transcription factors promote calciuminduced apoptosis in T cells and are regulated by MAP kinases and histone deacetylases. Synaptic vesicle endocytosis is coordinated by dephosphins, which are coordinately dephosphorylated on calmodulin- and calcineurinmodulated calcium influx. Genes annotated in NetAffx as androgen related Genes upregulated in response to glutamine starvation Glycolysis related genes Genes involved in glycogen metabolism Genes upregulated in response to leucine starvation Genes related to carbon fixation in photosynthetic organisms The interferon gamma pathway resembles the JAKSTAT pathway and activates STAT transcription factors. Type I interferon is an antiviral cytokine that induces a JAK-STAT type pathway leading to ISGF3 activation and a cellular antiviral response. Tricarboxylic acid related genes 1 22. Arf 23. Cbl 24. Ctla4 25. Fxr 26. Ifna 27. Intrinsic 28. Leptin 29. Pgc1a 30. Rarrxr 31. Calcineurin 32. Caspase 33. Sodd 34. Keratinocyte 35. VIP Cyclin-dependent kinase inhibitor 2A is a tumor suppressor that induces G1 arrest and can activate the p53 pathway, leading to G2/M arrest. Activated EGF receptors undergo endocytosis into clathrin-coated vesicles, where they are recycled to the membrane or ubiquitinated by Cbl. T cell activation requires interaction with an antigen-MHC-I complex on an antigen-presenting cell (APC), as well as CD28 interaction with the APC's CD80 or 86. The nuclear receptor transcription factors FXR and LXR are activated by cholesterol metabolites and regulate cholesterol homeostasis. Interferon alpha, active in the immune response, binds to the IFN receptor and activates Jak1 and Tyk2, which phosphorylate Stat1 and Stat2. The intrinsic prothrombin activation pathway is activated by traumatized blood vessels and induces clot formation. Leptin is a peptide secreted by adipose tissue that, in skeletal muscle, promotes fatty acid oxidation, decreases cells' lipid content, and promotes insulin sensitivity. PCG-1a is expressed in skeletal muscle, heart muscle, and brown fat, and is a coactivator for receptors such as glucocorticoid receptor and thyroid hormone receptor. RXR and RAR suppress transcription in the absence of ligand and, on binding trans- or 9-cisretinoic acid, are ubiquitinated to allow transcription to proceed. Increased intracellular calcium activates the phosphatase calcineurin in differentiating keratinocytes. Caspases are cysteine proteases active in apoptosis; caspase-8 and 9 cleave and activate other caspases, while 3, 6, and 7 cleave cellular targets. Some members of the tumor necrosis factor receptor family have cytoplasmic death domains that promote apoptosis when active and are repressed by silencers called SODDs. Keratinocyte differentiation, which models the differentiation of epidermal cells, requires the four main MAP kinase pathways. Apoptosis of activated T cells is inhibited by vasoactive intestinal peptide (VIP) and its relative 2 36. Proteasome 37. Akap13 38. GPCRs_Class_C_Metabotropic_ Glutamate_Pheromone 39. Par1 40. Pentose_Phosphate 41. Glycolysis 42. Mef2d 43. Eryth 44. Prostaglandin_and_Leukotriene_ Metabolism 45. Androgen_genes 46. Cell_Adhesion_Molecule_ Activity 47. Nos1 48. GABA 49. Inflam 50. Reductive_Carboxylate_Cycle_ CO2_Fixation 51. Proteasome PACAP. Ubiquitinated proteins are targeted for proteolytic degradation by the proteasome, where they are unfolded and degraded to small peptides in an ATP-dependent process. A-kinase anchor protein 13 (AKAP13) localizes protein kinase A holoenzyme and is a nucleotide exchange factor for Rho/Rac. The group of G-protein coupled receptors that are structurally/functionally related to the metabotropic glutamate receptors Activated extracellular thrombin cleaves and activates the G-protein coupled receptors PAR1 and PAR4, which activate platelets. Pentose Phosphate Pathway Glycolysis is an evolutionarily conserved pathway by which one glucose molecule is converted to two pyruvate molecules for a gain of 2 ATP. Mef2 transcription factors promote calciuminduced apoptosis in T cells and are regulated by MAP kinases and histone deacetylases. Erythropoietin selectively stimulates erythrocyte differentiation from CFU-GEMM cells in bone marrow. Genes related to prostaglandin and leukotriene metabolism Genes annotated in NetAffx as androgen related Obsolete by GO - mediates the adhesion of the cell to other cells or to the extracellular matrix. Glutamate stimulates NMDA-mediates calcium influx, which promotes nitric oxide synthesis from arginine by neuronal nitric oxide synthase, activating guanylate cyclase. Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter whose receptor is regulated by Plic-1, gephyrin, and GABARAP, which promote receptor clustering. Interleukins and TNF serve as signals to coordinate the inflammatory response, in which macrophages recruit and activate neutrophils, fibroblasts, and T cells. Reductive carboxylate cycle CO2 fixation related genes Ubiquitinated proteins are targeted for proteolytic degradation by the proteasome, where they are unfolded and degraded to small peptides in an 3 52. p35_Alzheimers 53. GLUCO 54. FBW7 55. Arginine_and_Proline_ Metabolism 56. Tert 57. Eif2 58. IL12 59. Pgc1a 60. Human_CD34_Enriched_ Transcription_Factors 61. HDAC 62. Glycolosis_and_Gluconeogenesis 63. G2 64. PS1 65. CR CAM 66. Spry 67. Mitr ATP-dependent process. p35, a neuron-specific activator of cyclindependent kinase 5, is cleaved to p25 in Alzheimer's disease and promotes hyperphosphorylated tau formation and apoptosis. Genes involved in glucose processing Cyclin E interacts with cell cycle checkpoint kinase cdk2 to allow transcription of genes required for S phase, including transcription of additional cyclin E. Genes involved in arginie and proline metabolism hTERC, the RNA subunit of telomerase, and hTERT, the catalytic protein subunit, are required for telomerase activity and are overexpressed in many cancers. Eukaryotic initiation factor 2 (EIF2) initiates translation by transferring Met-tRNA to the 40S ribosome in a GTP-dependent process. IL12 and Stat4 Dependent Signaling Pathway in Th1 Development PCG-1a is expressed in skeletal muscle, heart muscle, and brown fat, and is a coactivator for receptors such as glucocorticoid receptor and thyroid hormone receptor. Human CD34 enriched transcription factors related genes Myocyte enhancer factor MEF2 activates transcription of genes required for muscle cell differentiation and is inhibited by histone deacetylases. Genes involved in glycolysis and gluconeogenesis Activated Cdc2-cyclin B kinase regulates the G2/M transition; DNA damage stimulates the DNAPK/ATM/ATR kinases, which inactivate Cdc2. Presenilin is required for gamma-secretase activity to activate Notch signaling; presenilin also inhibits beta-catenin in the Wnt/Frizzled pathway. PNAS 2002: Cancer related genes involved in cell adhesion and metalloproteinases Four members of the Sprouty protein family block proliferative EGF signals by binding Grb-2, preventing Ras and MAP kinase activation. The MyoD/MEF2 transcription factors induce muscle cell differentiation and are repressed by the 4 68. Ctla4 69. Bile_acid_biosynthesis 70. MalateX 71. Ndk_Dynamin 72. p53 73. Type_III_secretion_system 74. ATP_synthesis 75. ROS 76. TCA 77. VIP 78. Cdc25 79. RB 80. Arf transcriptional repressor MITR. T cell activation requires interaction with an antigen-MHC-I complex on an antigen-presenting cell (APC), as well as CD28 interaction with the APC's CD80 or 86. Genes involved in bile acid biosynthesis The tricarboxylate transfer pathway shuttles acetyl groups of acetyl-CoA between mitochondria and the cytoplasm. Synaptic vesicle endocytosis is coordinated by dephosphins, which are coordinately dephosphorylated on calmodulin- and calcineurinmodulated calcium influx. p53 induces cell cycle arrest or apoptosis under conditions of DNA damage. Type III secretion system related genes Genes involved in ATP synthesis Reactive oxidative species related genes Tricarboxylic acid related genes Apoptosis of activated T cells is inhibited by vasoactive intestinal peptide (VIP) and its relative PACAP. The protein phosphatase Cdc25 is phosphorylated by Chk1 and activates Cdc2 to stimulate eukaryotic cells into M phase. The ATM protein kinase recognizes DNA damage and blocks cell cycle progression by phosphorylating chk1 and p53, which normally inhibits Rb to allow G1/S transitions. Cyclin-dependent kinase inhibitor 2A is a tumor suppressor that induces G1 arrest and can activate the p53 pathway, leading to G2/M arrest. 5