KEGG   PATHWAY: ccan04066
Entry
ccan04066                   Pathway                                
Name
HIF-1 signaling pathway - Castor canadensis (American beaver)
Description
Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that functions as a master regulator of oxygen homeostasis. It consists of two subunits: an inducibly-expressed HIF-1alpha subunit and a constitutively-expressed HIF-1beta subunit. Under normoxia, HIF-1 alpha undergoes hydroxylation at specific prolyl residues which leads to an immediate ubiquitination and subsequent proteasomal degradation of the subunit. In contrast, under hypoxia, HIF-1 alpha subunit becomes stable and interacts with coactivators such as p300/CBP to modulate its transcriptional activity. Eventually, HIF-1 acts as a master regulator of numerous hypoxia-inducible genes under hypoxic conditions. The target genes of HIF-1 encode proteins that increase O2 delivery and mediate adaptive responses to O2 deprivation. Despite its name, HIF-1 is induced not only in response to reduced oxygen availability but also by other stimulants, such as nitric oxide, or various growth factors.
Class
Environmental Information Processing; Signal transduction
Pathway map
ccan04066  HIF-1 signaling pathway
ccan04066

Organism
Castor canadensis (American beaver) [GN:ccan]
Gene
109679557  Il6; interleukin-6 [KO:K05405]
109688039  Il6r; interleukin-6 receptor subunit alpha [KO:K05055]
109687324  Stat3; signal transducer and activator of transcription 3 isoform X1 [KO:K04692]
109700701  Tlr4; toll-like receptor 4 isoform X1 [KO:K10160]
109676142  Ifng; interferon gamma [KO:K04687]
109697033  Ifngr1; LOW QUALITY PROTEIN: interferon gamma receptor 1 [KO:K05132]
109686803  Ifngr2; interferon gamma receptor 2 [KO:K05133]
109687142  Rela; transcription factor p65 isoform X1 [KO:K04735]
109682963  Nfkb1; nuclear factor NF-kappa-B p105 subunit [KO:K02580]
109689794  insulin [KO:K04526]
109700925  Egf; LOW QUALITY PROTEIN: pro-epidermal growth factor [KO:K04357]
109677734  insulin-like growth factor I [KO:K05459]
109697466  Igf1; insulin-like growth factor I [KO:K05459]
109694006  Insr; LOW QUALITY PROTEIN: insulin receptor [KO:K04527] [EC:2.7.10.1]
109693753  Egfr; epidermal growth factor receptor isoform X1 [KO:K04361] [EC:2.7.10.1]
109687530  insulin-like growth factor 1 receptor [KO:K05087] [EC:2.7.10.1]
109693877  Erbb2; receptor tyrosine-protein kinase erbB-2 [KO:K05083] [EC:2.7.10.1]
109687824  Map2k1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
109687808  Map2k2; dual specificity mitogen-activated protein kinase kinase 2 isoform X1 [KO:K04369] [EC:2.7.12.2]
109683259  Mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
109684381  Mapk1; mitogen-activated protein kinase 1 isoform X1 [KO:K04371] [EC:2.7.11.24]
109695463  Mknk1; MAP kinase-interacting serine/threonine-protein kinase 1 isoform X1 [KO:K04372] [EC:2.7.11.1]
109698290  MAP kinase-interacting serine/threonine-protein kinase 2-like isoform X1 [KO:K04372] [EC:2.7.11.1]
109698867  Mknk2; MAP kinase-interacting serine/threonine-protein kinase 2 [KO:K04372] [EC:2.7.11.1]
109681900  Pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
109689664  Pik3ca; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
109682432  Pik3r3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
109694666  Pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
109682554  phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
109688536  Akt2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
109691810  Akt1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
109686235  Akt3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
109689656  Mtor; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
109688934  Eif4ebp1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
109693543  Eif4e; eukaryotic translation initiation factor 4E [KO:K03259]
109692285  Eif4e2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
109685780  Eif4e1b; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
109688624  Rps6kb2; ribosomal protein S6 kinase beta-2 [KO:K04688] [EC:2.7.11.1]
109685124  Rps6kb1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
109698298  Rps6; 40S ribosomal protein S6 [KO:K02991]
109682911  Hif1a; hypoxia-inducible factor 1-alpha isoform X1 [KO:K08268]
109688948  Vhl; LOW QUALITY PROTEIN: von Hippel-Lindau disease tumor suppressor [KO:K03871]
109686914  Rbx1; E3 ubiquitin-protein ligase RBX1 [KO:K03868] [EC:2.3.2.32]
109692112  Eloc; transcription elongation factor B polypeptide 1 isoform X1 [KO:K03872]
109698691  Elob; transcription elongation factor B polypeptide 2 [KO:K03873]
109701020  Cul2; LOW QUALITY PROTEIN: cullin-2 [KO:K03870]
109694610  Egln1; egl nine homolog 1 isoform X1 [KO:K09592] [EC:1.14.11.29]
109697661  Egln2; egl nine homolog 2 [KO:K09592] [EC:1.14.11.29]
109697177  Egln3; egl nine homolog 3 [KO:K09592] [EC:1.14.11.29]
109681203  Arnt; aryl hydrocarbon receptor nuclear translocator isoform X1 [KO:K09097]
109681682  Crebbp; CREB-binding protein isoform X1 [KO:K04498] [EC:2.3.1.48]
109690951  Ep300; histone acetyltransferase p300 [KO:K04498] [EC:2.3.1.48]
109698413  cytochrome b-245 heavy chain [KO:K21421] [EC:1.-.-.-]
109683399  Plcg1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 [KO:K01116] [EC:3.1.4.11]
109696649  Plcg2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 [KO:K05859] [EC:3.1.4.11]
109687351  Prkca; protein kinase C alpha type isoform X1 [KO:K02677] [EC:2.7.11.13]
109683738  Prkcb; protein kinase C beta type [KO:K19662] [EC:2.7.11.13]
109693140  Prkcg; protein kinase C gamma type isoform X1 [KO:K19663] [EC:2.7.11.13]
109685908  calcium/calmodulin-dependent protein kinase type II subunit delta isoform X1 [KO:K04515] [EC:2.7.11.17]
109685909  calcium/calmodulin-dependent protein kinase type II subunit beta isoform X1 [KO:K04515] [EC:2.7.11.17]
109690704  Camk2a; calcium/calmodulin-dependent protein kinase type II subunit alpha isoform X1 [KO:K04515] [EC:2.7.11.17]
109696394  calcium/calmodulin-dependent protein kinase type II subunit gamma isoform X1 [KO:K04515] [EC:2.7.11.17]
109696671  Timp1; metalloproteinase inhibitor 1 [KO:K16451]
109682793  Ltbr; LOW QUALITY PROTEIN: tumor necrosis factor receptor superfamily member 3 [KO:K03159]
109687714  inhibitor of carbonic anhydrase-like [KO:K14736]
109687722  LOW QUALITY PROTEIN: serotransferrin-like [KO:K14736]
109694497  Tfrc; transferrin receptor protein 1 isoform X1 [KO:K06503]
109682127  Vegfa; vascular endothelial growth factor A isoform X1 [KO:K05448]
109694691  Flt1; vascular endothelial growth factor receptor 1 isoform X1 [KO:K05096] [EC:2.7.10.1]
109692813  Serpine1; plasminogen activator inhibitor 1 [KO:K03982]
109702790  LOW QUALITY PROTEIN: angiopoietin-1-like [KO:K05465]
109697772  Angpt2; angiopoietin-2 isoform X1 [KO:K05466]
109698999  Angpt4; angiopoietin-4 [KO:K05467]
109686627  Tek; angiopoietin-1 receptor isoform X1 [KO:K05121] [EC:2.7.10.1]
109676387  Edn1; endothelin-1 [KO:K16366]
109693015  Nos2; nitric oxide synthase, inducible [KO:K13241] [EC:1.14.13.39]
109694442  Nos3; nitric oxide synthase, endothelial isoform X1 [KO:K13242] [EC:1.14.13.39]
109692950  Hmox1; heme oxygenase 1 [KO:K00510] [EC:1.14.14.18]
109697786  Nppa; natriuretic peptides A [KO:K12334]
109674851  Slc2a1; solute carrier family 2, facilitated glucose transporter member 1 [KO:K07299]
109699522  Pdk1; pyruvate dehydrogenase (acetyl-transferring) kinase isozyme 1, mitochondrial [KO:K12077] [EC:2.7.11.2]
109685239  Hk1; hexokinase-1 [KO:K00844] [EC:2.7.1.1]
109697922  Hk2; hexokinase-2 isoform X1 [KO:K00844] [EC:2.7.1.1]
109684938  Hkdc1; LOW QUALITY PROTEIN: putative hexokinase HKDC1 [KO:K00844] [EC:2.7.1.1]
109685772  Hk3; hexokinase-3 isoform X1 [KO:K00844] [EC:2.7.1.1]
109689137  Pfkl; ATP-dependent 6-phosphofructokinase, liver type [KO:K00850] [EC:2.7.1.11]
109691605  Pfkm; ATP-dependent 6-phosphofructokinase, muscle type [KO:K00850] [EC:2.7.1.11]
109684798  Pfkp; ATP-dependent 6-phosphofructokinase, platelet type isoform X1 [KO:K00850] [EC:2.7.1.11]
109682800  Gapdh; glyceraldehyde-3-phosphate dehydrogenase [KO:K00134] [EC:1.2.1.12]
109696255  Aldob; fructose-bisphosphate aldolase B [KO:K01623] [EC:4.1.2.13]
109683233  Aldoa; LOW QUALITY PROTEIN: fructose-bisphosphate aldolase A [KO:K01623] [EC:4.1.2.13]
109685869  Aldoc; fructose-bisphosphate aldolase C [KO:K01623] [EC:4.1.2.13]
109682336  Eno1; alpha-enolase isoform X1 [KO:K01689] [EC:4.2.1.11]
109682775  Eno2; gamma-enolase [KO:K01689] [EC:4.2.1.11]
109684740  Eno3; beta-enolase [KO:K01689] [EC:4.2.1.11]
109690985  LOW QUALITY PROTEIN: phosphoglycerate kinase 2-like [KO:K00927] [EC:2.7.2.3]
109690989  phosphoglycerate kinase 2-like [KO:K00927] [EC:2.7.2.3]
109690990  phosphoglycerate kinase 2 [KO:K00927] [EC:2.7.2.3]
109699080  Pfkfb3; 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase 3 isoform X1 [KO:K01103] [EC:2.7.1.105 3.1.3.46]
109681913  L-lactate dehydrogenase A-like 6A [KO:K00016] [EC:1.1.1.27]
109696003  L-lactate dehydrogenase C chain-like [KO:K00016] [EC:1.1.1.27]
109696004  L-lactate dehydrogenase A chain [KO:K00016] [EC:1.1.1.27]
109684213  Ldhb; L-lactate dehydrogenase B chain [KO:K00016] [EC:1.1.1.27]
109675684  LOW QUALITY PROTEIN: L-lactate dehydrogenase A chain-like [KO:K00016] [EC:1.1.1.27]
109693757  Bcl2; apoptosis regulator Bcl-2 [KO:K02161]
109696503  Cdkn1a; cyclin-dependent kinase inhibitor 1 [KO:K06625]
109701269  Cdkn1b; cyclin-dependent kinase inhibitor 1B [KO:K06624]
109688063  pyruvate dehydrogenase E1 component subunit alpha, somatic form, mitochondrial [KO:K00161] [EC:1.2.4.1]
109703069  pyruvate dehydrogenase E1 component subunit alpha, mitochondrial-like isoform X1 [KO:K00161] [EC:1.2.4.1]
109697255  Pdhb; pyruvate dehydrogenase E1 component subunit beta, mitochondrial [KO:K00162] [EC:1.2.4.1]
Compound
C00002  ATP
C00007  Oxygen
C00022  Pyruvate
C00024  Acetyl-CoA
C00026  2-Oxoglutarate
C00031  D-Glucose
C00072  Ascorbate
C00076  Calcium cation
C00165  Diacylglycerol
C00186  (S)-Lactate
C00338  Lipopolysaccharide
C00533  Nitric oxide
C00704  Superoxide
C01245  D-myo-Inositol 1,4,5-trisphosphate
C14818  Fe2+
Reference
PMID:20836033
  Authors
Semenza GL
  Title
Oxygen homeostasis.
  Journal
Wiley Interdiscip Rev Syst Biol Med 2:336-61 (2010)
DOI:10.1002/wsbm.69
Reference
PMID:17955264
  Authors
Mole DR, Ratcliffe PJ
  Title
Cellular oxygen sensing in health and disease.
  Journal
Pediatr Nephrol 23:681-94 (2008)
DOI:10.1007/s00467-007-0632-x
Reference
PMID:18498744
  Authors
Kaelin WG Jr, Ratcliffe PJ
  Title
Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway.
  Journal
Mol Cell 30:393-402 (2008)
DOI:10.1016/j.molcel.2008.04.009
Reference
PMID:22205687
  Authors
Palazon A, Aragones J, Morales-Kastresana A, de Landazuri MO, Melero I
  Title
Molecular pathways: hypoxia response in immune cells fighting or promoting cancer.
  Journal
Clin Cancer Res 18:1207-13 (2012)
DOI:10.1158/1078-0432.CCR-11-1591
Reference
PMID:20965423
  Authors
Majmundar AJ, Wong WJ, Simon MC
  Title
Hypoxia-inducible factors and the response to hypoxic stress.
  Journal
Mol Cell 40:294-309 (2010)
DOI:10.1016/j.molcel.2010.09.022
Reference
PMID:22562152
  Authors
Greer SN, Metcalf JL, Wang Y, Ohh M
  Title
The updated biology of hypoxia-inducible factor.
  Journal
EMBO J 31:2448-60 (2012)
DOI:10.1038/emboj.2012.125
Reference
PMID:15448722
  Authors
Zagorska A, Dulak J
  Title
HIF-1: the knowns and unknowns of hypoxia sensing.
  Journal
Acta Biochim Pol 51:563-85 (2004)
Reference
PMID:19364912
  Authors
Semenza GL
  Title
Regulation of oxygen homeostasis by hypoxia-inducible factor 1.
  Journal
Physiology (Bethesda) 24:97-106 (2009)
DOI:10.1152/physiol.00045.2008
Reference
PMID:16234508
  Authors
Wenger RH, Stiehl DP, Camenisch G
  Title
Integration of oxygen signaling at the consensus HRE.
  Journal
Sci STKE 2005:re12 (2005)
DOI:10.1126/stke.3062005re12
Reference
PMID:15031665
  Authors
Lee JW, Bae SH, Jeong JW, Kim SH, Kim KW
  Title
Hypoxia-inducible factor (HIF-1)alpha: its protein stability and biological functions.
  Journal
Exp Mol Med 36:1-12 (2004)
DOI:10.1038/emm.2004.1
Reference
PMID:18259201
  Authors
Weidemann A, Johnson RS
  Title
Biology of HIF-1alpha.
  Journal
Cell Death Differ 15:621-7 (2008)
DOI:10.1038/cdd.2008.12
Reference
PMID:11902584
  Authors
Harris AL
  Title
Hypoxia--a key regulatory factor in tumour growth.
  Journal
Nat Rev Cancer 2:38-47 (2002)
DOI:10.1038/nrc704
Reference
PMID:19147540
  Authors
Knaup KX, Jozefowski K, Schmidt R, Bernhardt WM, Weidemann A, Juergensen JS, Warnecke C, Eckardt KU, Wiesener MS
  Title
Mutual regulation of hypoxia-inducible factor and mammalian target of rapamycin as a function of oxygen availability.
  Journal
Mol Cancer Res 7:88-98 (2009)
DOI:10.1158/1541-7786.MCR-08-0288
Reference
PMID:18505681
  Authors
Kaluz S, Kaluzova M, Stanbridge EJ
  Title
Regulation of gene expression by hypoxia: integration of the HIF-transduced hypoxic signal at the hypoxia-responsive element.
  Journal
Clin Chim Acta 395:6-13 (2008)
DOI:10.1016/j.cca.2008.05.002
Reference
PMID:20679415
  Authors
Cadenas S, Aragones J, Landazuri MO
  Title
Mitochondrial reprogramming through cardiac oxygen sensors in ischaemic heart disease.
  Journal
Cardiovasc Res 88:219-28 (2010)
DOI:10.1093/cvr/cvq256
Reference
PMID:19861159
  Authors
Berchner-Pfannschmidt U, Tug S, Kirsch M, Fandrey J
  Title
Oxygen-sensing under the influence of nitric oxide.
  Journal
Cell Signal 22:349-56 (2010)
DOI:10.1016/j.cellsig.2009.10.004
Related
pathway
ccan00020  Citrate cycle (TCA cycle)
ccan04010  MAPK signaling pathway
ccan04020  Calcium signaling pathway
ccan04120  Ubiquitin mediated proteolysis
ccan04150  mTOR signaling pathway
ccan04151  PI3K-Akt signaling pathway
ccan04370  VEGF signaling pathway
KO pathway
ko04066   
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