KEGG   PATHWAY: tmu04066
Entry
tmu04066                    Pathway                                
Name
HIF-1 signaling pathway - Trichechus manatus latirostris (Florida manatee)
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
tmu04066  HIF-1 signaling pathway
tmu04066

Organism
Trichechus manatus latirostris (Florida manatee) [GN:tmu]
Gene
101351590  interleukin-6 [KO:K05405]
101356003  interleukin-6 receptor subunit alpha isoform X1 [KO:K05055]
101342651  signal transducer and activator of transcription 3 isoform X3 [KO:K04692]
101353470  toll-like receptor 4 [KO:K10160]
101346429  interferon gamma [KO:K04687]
101345582  interferon gamma receptor 1 isoform X1 [KO:K05132]
101361970  interferon gamma receptor 2 [KO:K05133]
101361706  transcription factor p65 [KO:K04735]
101351866  nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
101346705  insulin [KO:K04526]
101355971  pro-epidermal growth factor [KO:K04357]
101361934  insulin-like growth factor I isoform X1 [KO:K05459]
101360415  insulin receptor [KO:K04527] [EC:2.7.10.1]
101356822  epidermal growth factor receptor isoform X1 [KO:K04361] [EC:2.7.10.1]
101355333  insulin-like growth factor 1 receptor [KO:K05087] [EC:2.7.10.1]
101354844  receptor tyrosine-protein kinase erbB-2 isoform X1 [KO:K05083] [EC:2.7.10.1]
101343332  dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
101341078  dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
101340589  mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
101358526  mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
101352604  MAP kinase-interacting serine/threonine-protein kinase 1 isoform X4 [KO:K04372] [EC:2.7.11.1]
101351154  MAP kinase-interacting serine/threonine-protein kinase 2 [KO:K04372] [EC:2.7.11.1]
101358678  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
101346849  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
101359658  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X2 [KO:K00922] [EC:2.7.1.153]
101351035  phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
101343804  phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
101347746  phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
101360493  RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
101356099  RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
101350197  RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
101343808  serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
101361891  eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
101357351  eukaryotic translation initiation factor 4E type 1B [KO:K03259]
101352426  eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
101351130  eukaryotic translation initiation factor 4E [KO:K03259]
101343535  ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
101354510  ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
101348417  40S ribosomal protein S6 [KO:K02991]
101347136  hypoxia-inducible factor 1-alpha isoform X1 [KO:K08268]
101352062  von Hippel-Lindau disease tumor suppressor isoform X1 [KO:K03871]
101349359  E3 ubiquitin-protein ligase RBX1 isoform X1 [KO:K03868] [EC:2.3.2.32]
101358566  elongin-C [KO:K03872]
101360743  elongin-B [KO:K03873]
101355736  cullin-2 isoform X1 [KO:K03870]
101359457  egl nine homolog 3 [KO:K09592] [EC:1.14.11.29]
101351991  egl nine homolog 2 [KO:K09592] [EC:1.14.11.29]
101361248  egl nine homolog 1 isoform X1 [KO:K09592] [EC:1.14.11.29]
101340519  aryl hydrocarbon receptor nuclear translocator [KO:K09097]
101344282  CREB-binding protein [KO:K04498] [EC:2.3.1.48]
101349614  histone acetyltransferase p300 [KO:K04498] [EC:2.3.1.48]
101344219  cytochrome b-245 heavy chain isoform X1 [KO:K21421] [EC:1.-.-.-]
101359597  1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 isoform X2 [KO:K01116] [EC:3.1.4.11]
101346393  1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 isoform X1 [KO:K05859] [EC:3.1.4.11]
101348250  protein kinase C alpha type isoform X2 [KO:K02677] [EC:2.7.11.13]
101356454  protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
101351254  protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
101359224  calcium/calmodulin-dependent protein kinase type II subunit alpha [KO:K04515] [EC:2.7.11.17]
101353435  calcium/calmodulin-dependent protein kinase type II subunit delta isoform X1 [KO:K04515] [EC:2.7.11.17]
101353082  calcium/calmodulin-dependent protein kinase type II subunit beta [KO:K04515] [EC:2.7.11.17]
101361961  calcium/calmodulin-dependent protein kinase type II subunit gamma [KO:K04515] [EC:2.7.11.17]
101353813  metalloproteinase inhibitor 1 [KO:K16451]
101350096  tumor necrosis factor receptor superfamily member 3 [KO:K03159]
101346088  erythropoietin isoform X1 [KO:K05437]
101362044  LOW QUALITY PROTEIN: serotransferrin [KO:K14736]
101340471  serotransferrin [KO:K14736]
101357703  transferrin receptor protein 1 isoform X1 [KO:K06503]
101341920  vascular endothelial growth factor A [KO:K05448]
101352737  vascular endothelial growth factor receptor 1 [KO:K05096] [EC:2.7.10.1]
101348466  plasminogen activator inhibitor 1 [KO:K03982]
101344008  angiopoietin-1 isoform X1 [KO:K05465]
101341636  angiopoietin-2 [KO:K05466]
101342215  angiopoietin-4 [KO:K05467]
101351895  angiopoietin-1 receptor isoform X1 [KO:K05121] [EC:2.7.10.1]
101349561  endothelin-1 [KO:K16366]
101356579  nitric oxide synthase, inducible [KO:K13241] [EC:1.14.13.39]
101356953  nitric oxide synthase, endothelial isoform X1 [KO:K13242] [EC:1.14.13.39]
101351050  heme oxygenase 1 [KO:K00510] [EC:1.14.14.18]
101359460  natriuretic peptides A [KO:K12334]
101346113  solute carrier family 2, facilitated glucose transporter member 1 [KO:K07299]
101341826  pyruvate dehydrogenase (acetyl-transferring) kinase isozyme 1, mitochondrial [KO:K12077] [EC:2.7.11.2]
101342288  hexokinase-2 isoform X1 [KO:K00844] [EC:2.7.1.1]
101357104  hexokinase-3 [KO:K00844] [EC:2.7.1.1]
101358528  hexokinase-1 isoform X2 [KO:K00844] [EC:2.7.1.1]
101358789  putative hexokinase HKDC1 isoform X1 [KO:K00844] [EC:2.7.1.1]
101345312  ATP-dependent 6-phosphofructokinase, liver type [KO:K00850] [EC:2.7.1.11]
101352081  ATP-dependent 6-phosphofructokinase, platelet type [KO:K00850] [EC:2.7.1.11]
101342778  ATP-dependent 6-phosphofructokinase, muscle type [KO:K00850] [EC:2.7.1.11]
101350847  glyceraldehyde-3-phosphate dehydrogenase [KO:K00134] [EC:1.2.1.12]
101359839  fructose-bisphosphate aldolase C [KO:K01623] [EC:4.1.2.13]
101341945  fructose-bisphosphate aldolase A isoform X2 [KO:K01623] [EC:4.1.2.13]
101356102  fructose-bisphosphate aldolase B [KO:K01623] [EC:4.1.2.13]
101358342  alpha-enolase [KO:K01689] [EC:4.2.1.11]
101346571  beta-enolase [KO:K01689] [EC:4.2.1.11]
101356999  gamma-enolase [KO:K01689] [EC:4.2.1.11]
101346918  phosphoglycerate kinase 1 [KO:K00927] [EC:2.7.2.3]
101357256  phosphoglycerate kinase 2 [KO:K00927] [EC:2.7.2.3]
101356475  6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase 3 isoform X2 [KO:K01103] [EC:2.7.1.105 3.1.3.46]
101361915  L-lactate dehydrogenase A chain isoform X2 [KO:K00016] [EC:1.1.1.27]
101340675  L-lactate dehydrogenase C chain isoform X1 [KO:K00016] [EC:1.1.1.27]
101340938  L-lactate dehydrogenase A-like 6A [KO:K00016] [EC:1.1.1.27]
101358031  L-lactate dehydrogenase B chain [KO:K00016] [EC:1.1.1.27]
101347007  apoptosis regulator Bcl-2 isoform X1 [KO:K02161]
101342008  cyclin-dependent kinase inhibitor 1 isoform X2 [KO:K06625]
101360273  cyclin-dependent kinase inhibitor 1B [KO:K06624]
101343462  pyruvate dehydrogenase E1 component subunit alpha, testis-specific form, mitochondrial isoform X1 [KO:K00161] [EC:1.2.4.1]
101351614  pyruvate dehydrogenase E1 component subunit alpha, somatic form, mitochondrial [KO:K00161] [EC:1.2.4.1]
101341695  pyruvate dehydrogenase E1 component subunit beta, mitochondrial isoform X1 [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
tmu00020  Citrate cycle (TCA cycle)
tmu04010  MAPK signaling pathway
tmu04020  Calcium signaling pathway
tmu04120  Ubiquitin mediated proteolysis
tmu04150  mTOR signaling pathway
tmu04151  PI3K-Akt signaling pathway
tmu04370  VEGF signaling pathway
KO pathway
ko04066   
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