Entry Name HIF-1 signaling pathway
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 transductionBRITE hierarchy
Pathway map Orthology K00134 GAPDH, gapA; glyceraldehyde 3-phosphate dehydrogenase (phosphorylating) [EC:1.2.1.12 ]
K00161 PDHA; pyruvate dehydrogenase E1 component subunit alpha [EC:1.2.4.1 ]
K00162 PDHB; pyruvate dehydrogenase E1 component subunit beta [EC:1.2.4.1 ]
K00922 PIK3CA_B_D; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:2.7.1.153 ]
K01116 PLCG1; phosphatidylinositol phospholipase C, gamma-1 [EC:3.1.4.11 ]
K02161 BCL2; apoptosis regulator Bcl-2
K02580 NFKB1; nuclear factor NF-kappa-B p105 subunit
K02649 PIK3R1_2_3; phosphoinositide-3-kinase regulatory subunit alpha/beta/delta
K02991 RP-S6e, RPS6; small subunit ribosomal protein S6e
K03159 TNFRSF3, LTBR; lymphotoxin beta receptor TNFR superfamily member 3
K03259 EIF4E; translation initiation factor 4E
K03871 VHL; von Hippel-Lindau disease tumor supressor
K03982 SERPINE1, PAI1; plasminogen activator inhibitor 1
K04357 EGF; epidermal growth factor
K04368 MAP2K1, MEK1; mitogen-activated protein kinase kinase 1 [EC:2.7.12.2 ]
K04369 MAP2K2, MEK2; mitogen-activated protein kinase kinase 2 [EC:2.7.12.2 ]
K04372 MKNK, MNK; MAP kinase interacting serine/threonine kinase [EC:2.7.11.1 ]
K04515 CAMK2; calcium/calmodulin-dependent protein kinase (CaM kinase) II [EC:2.7.11.17 ]
K04692 STAT3; signal transducer and activator of transcription 3
K04735 RELA; transcription factor p65
K05055 IL6R, CD126; interleukin 6 receptor
K05083 ERBB2, HER2, CD340; receptor tyrosine-protein kinase erbB-2 [EC:2.7.10.1 ]
K05087 IGF1R, CD221; insulin-like growth factor 1 receptor [EC:2.7.10.1 ]
K05121 TEK, TIE2, CD202; endothelial-specific receptor tyrosine kinase [EC:2.7.10.1 ]
K05132 IFNGR1, CD119; interferon gamma receptor 1
K05133 IFNGR2; interferon gamma receptor 2
K05448 VEGFA; vascular endothelial growth factor A
K05459 IGF1; insulin-like growth factor 1
K05859 PLCG2; phosphatidylinositol phospholipase C, gamma-2 [EC:3.1.4.11 ]
K06503 TFRC, CD71; transferrin receptor
K06624 CDKN1B, P27, KIP1; cyclin-dependent kinase inhibitor 1B
K06625 CDKN1A, P21, CIP1; cyclin-dependent kinase inhibitor 1A
K07203 MTOR, FRAP, TOR; serine/threonine-protein kinase mTOR [EC:2.7.11.1 ]
K07205 EIF4EBP1; eukaryotic translation initiation factor 4E binding protein 1
K07299 SLC2A1, GLUT1; MFS transporter, SP family, solute carrier family 2 (facilitated glucose transporter), member 1
K08268 HIF1A; hypoxia-inducible factor 1 alpha
K09095 HIF2A, EPAS1; hypoxia-inducible factor 2 alpha
K09097 ARNT; aryl hydrocarbon receptor nuclear translocator
K10160 TLR4, CD284; toll-like receptor 4
K12334 NPPA; natriuretic peptide A
K16451 TIMP1; metalloproteinase inhibitor 1
K21421 NOX2, GP91, CYBB; NADPH oxidase 2 [EC:1.-.-.-]
Compound C01245 D-myo-Inositol 1,4,5-trisphosphate
Reference Authors Semenza GL
Title Oxygen homeostasis.
Journal Reference Authors Mole DR, Ratcliffe PJ
Title Cellular oxygen sensing in health and disease.
Journal Reference Authors Kaelin WG Jr, Ratcliffe PJ
Title Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway.
Journal Reference 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 Reference Authors Majmundar AJ, Wong WJ, Simon MC
Title Hypoxia-inducible factors and the response to hypoxic stress.
Journal Reference Authors Greer SN, Metcalf JL, Wang Y, Ohh M
Title The updated biology of hypoxia-inducible factor.
Journal Reference Authors Zagorska A, Dulak J
Title HIF-1: the knowns and unknowns of hypoxia sensing.
Journal Acta Biochim Pol 51:563-85 (2004)
Reference Authors Semenza GL
Title Regulation of oxygen homeostasis by hypoxia-inducible factor 1.
Journal Reference Authors Wenger RH, Stiehl DP, Camenisch G
Title Integration of oxygen signaling at the consensus HRE.
Journal Reference 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 Reference Authors Weidemann A, Johnson RS
Title Biology of HIF-1alpha.
Journal Reference Authors Harris AL
Title Hypoxia--a key regulatory factor in tumour growth.
Journal Reference 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 Reference 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 Reference Authors Cadenas S, Aragones J, Landazuri MO
Title Mitochondrial reprogramming through cardiac oxygen sensors in ischaemic heart disease.
Journal Reference Authors Berchner-Pfannschmidt U, Tug S, Kirsch M, Fandrey J
Title Oxygen-sensing under the influence of nitric oxide.
Journal Related ko04120 Ubiquitin mediated proteolysis
