KEGG   PATHWAY: mmu04066
Entry
mmu04066                    Pathway                                
Name
HIF-1 signaling pathway - Mus musculus (house mouse)
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
mmu04066  HIF-1 signaling pathway
mmu04066

Organism
Mus musculus (house mouse) [GN:mmu]
Gene
16193  Il6; interleukin 6 [KO:K05405]
16194  Il6ra; interleukin 6 receptor, alpha [KO:K05055]
20848  Stat3; signal transducer and activator of transcription 3 [KO:K04692]
21898  Tlr4; toll-like receptor 4 [KO:K10160]
15978  Ifng; interferon gamma [KO:K04687]
15979  Ifngr1; interferon gamma receptor 1 [KO:K05132]
15980  Ifngr2; interferon gamma receptor 2 [KO:K05133]
19697  Rela; v-rel reticuloendotheliosis viral oncogene homolog A (avian) [KO:K04735]
18033  Nfkb1; nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105 [KO:K02580]
16334  Ins2; insulin II [KO:K04526]
16333  Ins1; insulin I [KO:K04526]
13645  Egf; epidermal growth factor [KO:K04357]
16000  Igf1; insulin-like growth factor 1 [KO:K05459]
16337  Insr; insulin receptor [KO:K04527] [EC:2.7.10.1]
13649  Egfr; epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1]
16001  Igf1r; insulin-like growth factor I receptor [KO:K05087] [EC:2.7.10.1]
13866  Erbb2; erb-b2 receptor tyrosine kinase 2 [KO:K05083] [EC:2.7.10.1]
26395  Map2k1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
26396  Map2k2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
26413  Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
26417  Mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
17346  Mknk1; MAP kinase-interacting serine/threonine kinase 1 [KO:K04372] [EC:2.7.11.1]
17347  Mknk2; MAP kinase-interacting serine/threonine kinase 2 [KO:K04372] [EC:2.7.11.1]
18706  Pik3ca; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]
18707  Pik3cd; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
74769  Pik3cb; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:2.7.1.153]
18709  Pik3r2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
18708  Pik3r1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
18710  Pik3r3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
11651  Akt1; thymoma viral proto-oncogene 1 [KO:K04456] [EC:2.7.11.1]
11652  Akt2; thymoma viral proto-oncogene 2 [KO:K04456] [EC:2.7.11.1]
23797  Akt3; thymoma viral proto-oncogene 3 [KO:K04456] [EC:2.7.11.1]
56717  Mtor; mechanistic target of rapamycin kinase [KO:K07203] [EC:2.7.11.1]
13685  Eif4ebp1; eukaryotic translation initiation factor 4E binding protein 1 [KO:K07205]
13684  Eif4e; eukaryotic translation initiation factor 4E [KO:K03259]
26987  Eif4e2; eukaryotic translation initiation factor 4E member 2 [KO:K03259]
218268  Eif4e1b; eukaryotic translation initiation factor 4E family member 1B [KO:K03259]
58988  Rps6kb2; ribosomal protein S6 kinase, polypeptide 2 [KO:K04688] [EC:2.7.11.1]
72508  Rps6kb1; ribosomal protein S6 kinase, polypeptide 1 [KO:K04688] [EC:2.7.11.1]
20104  Rps6; ribosomal protein S6 [KO:K02991]
216036  Gm4796; predicted gene 4796 [KO:K02991]
15251  Hif1a; hypoxia inducible factor 1, alpha subunit [KO:K08268]
22346  Vhl; von Hippel-Lindau tumor suppressor [KO:K03871]
56438  Rbx1; ring-box 1 [KO:K03868] [EC:2.3.2.32]
67923  Eloc; elongin C [KO:K03872]
102631956  Gm30155; predicted gene, 30155 [KO:K03872]
102637110  Gm34005; predicted gene, 34005 [KO:K03872]
67673  Elob; elongin B [KO:K03873]
71745  Cul2; cullin 2 [KO:K03870]
112407  Egln3; egl-9 family hypoxia-inducible factor 3 [KO:K09592] [EC:1.14.11.29]
112406  Egln2; egl-9 family hypoxia-inducible factor 2 [KO:K09592] [EC:1.14.11.29]
112405  Egln1; egl-9 family hypoxia-inducible factor 1 [KO:K09592] [EC:1.14.11.29]
11863  Arnt; aryl hydrocarbon receptor nuclear translocator [KO:K09097]
12914  Crebbp; CREB binding protein [KO:K04498] [EC:2.3.1.48]
328572  Ep300; E1A binding protein p300 [KO:K04498] [EC:2.3.1.48]
13058  Cybb; cytochrome b-245, beta polypeptide [KO:K21421] [EC:1.-.-.-]
18803  Plcg1; phospholipase C, gamma 1 [KO:K01116] [EC:3.1.4.11]
234779  Plcg2; phospholipase C, gamma 2 [KO:K05859] [EC:3.1.4.11]
18750  Prkca; protein kinase C, alpha [KO:K02677] [EC:2.7.11.13]
18751  Prkcb; protein kinase C, beta [KO:K19662] [EC:2.7.11.13]
18752  Prkcg; protein kinase C, gamma [KO:K19663] [EC:2.7.11.13]
108058  Camk2d; calcium/calmodulin-dependent protein kinase II, delta [KO:K04515] [EC:2.7.11.17]
12325  Camk2g; calcium/calmodulin-dependent protein kinase II gamma [KO:K04515] [EC:2.7.11.17]
12323  Camk2b; calcium/calmodulin-dependent protein kinase II, beta [KO:K04515] [EC:2.7.11.17]
12322  Camk2a; calcium/calmodulin-dependent protein kinase II alpha [KO:K04515] [EC:2.7.11.17]
21857  Timp1; tissue inhibitor of metalloproteinase 1 [KO:K16451]
17000  Ltbr; lymphotoxin B receptor [KO:K03159]
13856  Epo; erythropoietin [KO:K05437]
22041  Trf; transferrin [KO:K14736]
71775  Inhca; inhibitor of carbonic anhydrase [KO:K14736]
22042  Tfrc; transferrin receptor [KO:K06503]
22339  Vegfa; vascular endothelial growth factor A [KO:K05448]
14254  Flt1; FMS-like tyrosine kinase 1 [KO:K05096] [EC:2.7.10.1]
18787  Serpine1; serine (or cysteine) peptidase inhibitor, clade E, member 1 [KO:K03982]
11600  Angpt1; angiopoietin 1 [KO:K05465]
11601  Angpt2; angiopoietin 2 [KO:K05466]
11602  Angpt4; angiopoietin 4 [KO:K05467]
21687  Tek; TEK receptor tyrosine kinase [KO:K05121] [EC:2.7.10.1]
13614  Edn1; endothelin 1 [KO:K16366]
18126  Nos2; nitric oxide synthase 2, inducible [KO:K13241] [EC:1.14.13.39]
18127  Nos3; nitric oxide synthase 3, endothelial cell [KO:K13242] [EC:1.14.13.39]
15368  Hmox1; heme oxygenase 1 [KO:K00510] [EC:1.14.14.18]
230899  Nppa; natriuretic peptide type A [KO:K12334]
20525  Slc2a1; solute carrier family 2 (facilitated glucose transporter), member 1 [KO:K07299]
228026  Pdk1; pyruvate dehydrogenase kinase, isoenzyme 1 [KO:K12077] [EC:2.7.11.2]
15277  Hk2; hexokinase 2 [KO:K00844] [EC:2.7.1.1]
212032  Hk3; hexokinase 3 [KO:K00844] [EC:2.7.1.1]
15275  Hk1; hexokinase 1 [KO:K00844] [EC:2.7.1.1]
216019  Hkdc1; hexokinase domain containing 1 [KO:K00844] [EC:2.7.1.1]
18641  Pfkl; phosphofructokinase, liver, B-type [KO:K00850] [EC:2.7.1.11]
18642  Pfkm; phosphofructokinase, muscle [KO:K00850] [EC:2.7.1.11]
56421  Pfkp; phosphofructokinase, platelet [KO:K00850] [EC:2.7.1.11]
14433  Gapdh; glyceraldehyde-3-phosphate dehydrogenase [KO:K00134] [EC:1.2.1.12]
115487111  Gm29667; predicted gene 29667 [KO:K00134] [EC:1.2.1.12]
11674  Aldoa; aldolase A, fructose-bisphosphate [KO:K01623] [EC:4.1.2.13]
230163  Aldob; aldolase B, fructose-bisphosphate [KO:K01623] [EC:4.1.2.13]
11676  Aldoc; aldolase C, fructose-bisphosphate [KO:K01623] [EC:4.1.2.13]
353204  Aldoart1; aldolase 1 A, retrogene 1 [KO:K01623] [EC:4.1.2.13]
79459  Aldoart2; aldolase 1 A, retrogene 2 [KO:K01623] [EC:4.1.2.13]
13806  Eno1; enolase 1, alpha non-neuron [KO:K01689] [EC:4.2.1.11]
13807  Eno2; enolase 2, gamma neuronal [KO:K01689] [EC:4.2.1.11]
13808  Eno3; enolase 3, beta muscle [KO:K01689] [EC:4.2.1.11]
433182  Eno1b; enolase 1B, retrotransposed [KO:K01689] [EC:4.2.1.11]
18655  Pgk1; phosphoglycerate kinase 1 [KO:K00927] [EC:2.7.2.3]
18663  Pgk2; phosphoglycerate kinase 2 [KO:K00927] [EC:2.7.2.3]
170768  Pfkfb3; 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 [KO:K01103] [EC:2.7.1.105 3.1.3.46]
16828  Ldha; lactate dehydrogenase A [KO:K00016] [EC:1.1.1.27]
16832  Ldhb; lactate dehydrogenase B [KO:K00016] [EC:1.1.1.27]
16833  Ldhc; lactate dehydrogenase C [KO:K00016] [EC:1.1.1.27]
106557  Ldhal6b; lactate dehydrogenase A-like 6B [KO:K00016] [EC:1.1.1.27]
12043  Bcl2; B cell leukemia/lymphoma 2 [KO:K02161]
12575  Cdkn1a; cyclin dependent kinase inhibitor 1A [KO:K06625]
12576  Cdkn1b; cyclin dependent kinase inhibitor 1B [KO:K06624]
18597  Pdha1; pyruvate dehydrogenase E1 alpha 1 [KO:K00161] [EC:1.2.4.1]
18598  Pdha2; pyruvate dehydrogenase E1 alpha 2 [KO:K00161] [EC:1.2.4.1]
68263  Pdhb; pyruvate dehydrogenase (lipoamide) beta [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
mmu00020  Citrate cycle (TCA cycle)
mmu04010  MAPK signaling pathway
mmu04020  Calcium signaling pathway
mmu04120  Ubiquitin mediated proteolysis
mmu04150  mTOR signaling pathway
mmu04151  PI3K-Akt signaling pathway
mmu04370  VEGF signaling pathway
KO pathway
ko04066   
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