KEGG   PATHWAY: rno04066
Entry
rno04066                    Pathway                                
Name
HIF-1 signaling pathway - Rattus norvegicus (rat)
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
rno04066  HIF-1 signaling pathway
rno04066

Organism
Rattus norvegicus (rat) [GN:rno]
Gene
24498  Il6; interleukin-6 precursor [KO:K05405]
24499  Il6r; interleukin-6 receptor subunit alpha precursor [KO:K05055]
25125  Stat3; signal transducer and activator of transcription 3 [KO:K04692]
29260  Tlr4; toll-like receptor 4 precursor [KO:K10160]
25712  Ifng; interferon gamma precursor [KO:K04687]
116465  Ifngr1; interferon gamma receptor 1 precursor [KO:K05132]
360697  Ifngr2; interferon gamma receptor 2 precursor [KO:K05133]
309165  Rela; transcription factor p65 [KO:K04735]
81736  Nfkb1; nuclear factor NF-kappa-B p105 subunit isoform 2 [KO:K02580]
24506  Ins2; insulin-2 preproprotein [KO:K04526]
24505  Ins1; insulin-1 preproprotein [KO:K04526]
25313  Egf; pro-epidermal growth factor precursor [KO:K04357]
24482  Igf1; insulin-like growth factor I isoform d preproprotein [KO:K05459]
24954  Insr; insulin receptor preproprotein [KO:K04527] [EC:2.7.10.1]
24329  Egfr; epidermal growth factor receptor isoform 2 precursor [KO:K04361] [EC:2.7.10.1]
25718  Igf1r; insulin-like growth factor 1 receptor isoform 2 precursor [KO:K05087] [EC:2.7.10.1]
24337  Erbb2; receptor tyrosine-protein kinase erbB-2 precursor [KO:K05083] [EC:2.7.10.1]
170851  Map2k1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
58960  Map2k2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
116590  Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
50689  Mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
299618  Mknk2; MAP kinase-interacting serine/threonine-protein kinase 2 [KO:K04372] [EC:2.7.11.1]
500526  Mknk1; MAP kinase-interacting serine/threonine-protein kinase 1 [KO:K04372] [EC:2.7.11.1]
85243  Pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
170911  Pik3ca; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
366508  Pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
134484121  LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform-like [KO:K00922] [EC:2.7.1.153]
25513  Pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]
60664  Pik3r3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
29741  Pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
24185  Akt1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
25233  Akt2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
29414  Akt3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
56718  Mtor; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
116636  Eif4ebp1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
117045  Eif4e; eukaryotic translation initiation factor 4E [KO:K03259]
686104  Eif4e1b; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
363275  Eif4e2; eukaryotic translation initiation factor 4E type 2 isoform 1 [KO:K03259]
83840  Rps6kb1; ribosomal protein S6 kinase beta-1 [KO:K04688] [EC:2.7.11.1]
361696  Rps6kb2; ribosomal protein S6 kinase beta-2 [KO:K04688] [EC:2.7.11.1]
29304  Rps6; small ribosomal subunit protein eS6 [KO:K02991]
29560  Hif1a; hypoxia-inducible factor 1-alpha [KO:K08268]
24874  Vhl; von Hippel-Lindau disease tumor suppressor [KO:K03871]
300084  Rbx1; E3 ubiquitin-protein ligase RBX1 [KO:K03868] [EC:2.3.2.32]
64525  Eloc; elongin-C [KO:K03872]
134482479  elongin-C-like [KO:K03872]
134482480  elongin-C-like [KO:K03872]
134482485  elongin-C-like [KO:K03872]
103691088  Elocl1; elongin-C-like [KO:K03872]
120097475  elongin-C-like [KO:K03872]
120099279  elongin-C-like [KO:K03872]
81807  Elob; elongin-B [KO:K03873]
134486081  elongin-B-like [KO:K03873]
120101893  Elob-ps3; elongin-B-like [KO:K03873]
134486082  elongin-B-like [KO:K03873]
690241  Elob-ps14; elongin-B-like [KO:K03873]
502620  Elob-ps8; elongin-B-like [KO:K03873]
134486083  elongin-B-like [KO:K03873]
120101899  Elob-ps15; elongin-B-like [KO:K03873]
134486084  elongin-B-like [KO:K03873]
120101894  Elob-ps13; elongin-B-like [KO:K03873]
120101896  Elob-ps7; elongin-B-like [KO:K03873]
120101895  Elob-ps5; elongin-B-like [KO:K03873]
134486085  elongin-B-like [KO:K03873]
361258  Cul2; cullin-2 [KO:K03870]
54702  Egln3; prolyl hydroxylase EGLN3 [KO:K09592] [EC:1.14.11.29]
308457  Egln2; prolyl hydroxylase EGLN2 [KO:K09592] [EC:1.14.11.29]
308913  Egln1; egl nine homolog 1 [KO:K09592] [EC:1.14.11.29]
25242  Arnt; aryl hydrocarbon receptor nuclear translocator isoform 1 [KO:K09097]
54244  Crebbp; histone lysine acetyltransferase CREBBP [KO:K04498] [EC:2.3.1.48]
170915  Ep300; histone acetyltransferase p300 isoform X1 [KO:K04498] [EC:2.3.1.48]
66021  Cybb; cytochrome b-245 beta chain [KO:K21421] [EC:1.-.-.-]
25738  Plcg1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 [KO:K01116] [EC:3.1.4.11]
29337  Plcg2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 [KO:K05859] [EC:3.1.4.11]
24680  Prkca; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
25023  Prkcb; protein kinase C beta type isoform 2 [KO:K19662] [EC:2.7.11.13]
24681  Prkcg; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
25400  Camk2a; calcium/calmodulin-dependent protein kinase type II subunit alpha [KO:K04515] [EC:2.7.11.17]
24246  Camk2d; calcium/calmodulin-dependent protein kinase type II subunit delta [KO:K04515] [EC:2.7.11.17]
24245  Camk2b; calcium/calmodulin-dependent protein kinase type II subunit beta isoform 2 [KO:K04515] [EC:2.7.11.17]
171140  Camk2g; calcium/calmodulin-dependent protein kinase type II subunit gamma [KO:K04515] [EC:2.7.11.17]
116510  Timp1; metalloproteinase inhibitor 1 precursor [KO:K16451]
297604  Ltbr; tumor necrosis factor receptor superfamily member 3 precursor [KO:K03159]
24335  Epo; erythropoietin precursor [KO:K05437]
24825  Tf; serotransferrin precursor [KO:K14736]
315963  Inhca; Inhibitor of carbonic anhydrase precursor [KO:K14736]
64678  Tfrc; transferrin receptor protein 1 [KO:K06503]
83785  Vegfa; vascular endothelial growth factor A isoform 6 precursor [KO:K05448]
54251  Flt1; vascular endothelial growth factor receptor 1 isoform 2 precursor [KO:K05096] [EC:2.7.10.1]
24617  Serpine1; plasminogen activator inhibitor 1 precursor [KO:K03982]
89807  Angpt1; angiopoietin-1 precursor [KO:K05465]
89805  Angpt2; angiopoietin-2 precursor [KO:K05466]
296269  Angpt4; angiopoietin-4 precursor [KO:K05467]
89804  Tek; angiopoietin-1 receptor [KO:K05121] [EC:2.7.10.1]
24323  Edn1; endothelin-1 preproprotein [KO:K16366]
24599  Nos2; nitric oxide synthase, inducible [KO:K13241] [EC:1.14.13.39]
24600  Nos3; nitric oxide synthase 3 [KO:K13242] [EC:1.14.13.39]
24451  Hmox1; heme oxygenase 1 [KO:K00510] [EC:1.14.14.18]
24602  Nppa; natriuretic peptides A precursor [KO:K12334]
24778  Slc2a1; solute carrier family 2, facilitated glucose transporter member 1 [KO:K07299]
116551  Pdk1; pyruvate dehydrogenase kinase, isozyme 1 precursor [KO:K12077] [EC:2.7.11.2]
25058  Hk1; hexokinase-1 isoform 2 [KO:K00844] [EC:2.7.1.1]
25059  Hk2; hexokinase-2 [KO:K00844] [EC:2.7.1.1]
25060  Hk3; hexokinase-3 [KO:K00844] [EC:2.7.1.1]
100364027  Hkdc1; hexokinase HKDC1 isoform X1 [KO:K00844] [EC:2.7.1.1]
65152  Pfkm; ATP-dependent 6-phosphofructokinase, muscle type [KO:K00850] [EC:2.7.1.11]
25741  Pfkl; ATP-dependent 6-phosphofructokinase, liver type [KO:K00850] [EC:2.7.1.11]
60416  Pfkp; ATP-dependent 6-phosphofructokinase, platelet type [KO:K00850] [EC:2.7.1.11]
24383  Gapdh; glyceraldehyde-3-phosphate dehydrogenase [KO:K00134] [EC:1.2.1.12]
303448  Gapdhl6; similar to glyceraldehyde-3-phosphate dehydrogenase [KO:K00134] [EC:1.2.1.12]
290604  Gapdhl10; glyceraldehyde-3-phosphate dehydrogenase-like [KO:K00134] [EC:1.2.1.12]
295423  Gapdhl9; glyceraldehyde-3-phosphate dehydrogenase-like [KO:K00134] [EC:1.2.1.12]
120101714  glyceraldehyde-3-phosphate dehydrogenase-like [KO:K00134] [EC:1.2.1.12]
120096209  glyceraldehyde-3-phosphate dehydrogenase-like [KO:K00134] [EC:1.2.1.12]
108352954  Gapdhl3; glyceraldehyde-3-phosphate dehydrogenase-like [KO:K00134] [EC:1.2.1.12]
108349792  Gapdhl2; glyceraldehyde-3-phosphate dehydrogenase-like [KO:K00134] [EC:1.2.1.12]
134480667  glyceraldehyde-3-phosphate dehydrogenase-like [KO:K00134] [EC:1.2.1.12]
134480898  glyceraldehyde-3-phosphate dehydrogenase-like [KO:K00134] [EC:1.2.1.12]
134483684  glyceraldehyde-3-phosphate dehydrogenase-like [KO:K00134] [EC:1.2.1.12]
134486952  glyceraldehyde-3-phosphate dehydrogenase [KO:K00134] [EC:1.2.1.12]
134487102  glyceraldehyde-3-phosphate dehydrogenase-like [KO:K00134] [EC:1.2.1.12]
24189  Aldoa; fructose-bisphosphate aldolase A [KO:K01623] [EC:4.1.2.13]
24191  Aldoc; fructose-bisphosphate aldolase C [KO:K01623] [EC:4.1.2.13]
24190  Aldob; fructose-bisphosphate aldolase B [KO:K01623] [EC:4.1.2.13]
299052  Aldoart2; fructose-bisphosphate aldolase [KO:K01623] [EC:4.1.2.13]
24333  Eno1; alpha-enolase [KO:K01689] [EC:4.2.1.11]
25438  Eno3; beta-enolase [KO:K01689] [EC:4.2.1.11]
24334  Eno2; gamma-enolase [KO:K01689] [EC:4.2.1.11]
24644  Pgk1; phosphoglycerate kinase 1 [KO:K00927] [EC:2.7.2.3]
316265  Pgk2; phosphoglycerate kinase 2 [KO:K00927] [EC:2.7.2.3]
499525  Pgk1l1; phosphoglycerate kinase 1-like [KO:K00927] [EC:2.7.2.3]
117276  Pfkfb3; 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase 3 [KO:K01103] [EC:2.7.1.105 3.1.3.46]
24533  Ldha; L-lactate dehydrogenase A chain [KO:K00016] [EC:1.1.1.27]
24534  Ldhb; L-lactate dehydrogenase B chain isoform Ldhb [KO:K00016] [EC:1.1.1.27]
29634  Ldhc; L-lactate dehydrogenase C chain [KO:K00016] [EC:1.1.1.27]
369018  Ldhal6b; L-lactate dehydrogenase A-like 6B [KO:K00016] [EC:1.1.1.27]
500965  Ldhal1; L-lactate dehydrogenase A chain-like [KO:K00016] [EC:1.1.1.27]
24224  Bcl2; apoptosis regulator Bcl-2 [KO:K02161]
114851  Cdkn1a; cyclin-dependent kinase inhibitor 1 [KO:K06625]
83571  Cdkn1b; cyclin-dependent kinase inhibitor 1B [KO:K06624]
117098  Pdha2; pyruvate dehydrogenase E1 component subunit alpha, testis-specific form, mitochondrial precursor [KO:K00161] [EC:1.2.4.1]
29554  Pdha1; pyruvate dehydrogenase E1 component subunit alpha, somatic form, mitochondrial precursor [KO:K00161] [EC:1.2.4.1]
289950  Pdhb; pyruvate dehydrogenase E1 component subunit beta, mitochondrial precursor [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
rno00020  Citrate cycle (TCA cycle)
rno04010  MAPK signaling pathway
rno04020  Calcium signaling pathway
rno04120  Ubiquitin mediated proteolysis
rno04150  mTOR signaling pathway
rno04151  PI3K-Akt signaling pathway
rno04370  VEGF signaling pathway
KO pathway
ko04066   
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