Molecule Information

General Information of the Molecule (ID: Mol04412)

• Name: Hypoxia-inducible factor 1-alpha (HIF1A) ,Homo sapiens
• Synonyms: ARNT-interacting protein; Basic-helix-loop-helix-PAS protein MOP1 ; Class E basic helix-loop-helix protein 78; Member of PAS protein 1 ; PAS domain-containing protein 8
• Molecule Type: Protein
• Gene Name: HIF1A
• Gene ID: 3091
• Sequence:
  MEGAGGANDKKKISSERRKEKSRDAARSRRSKESEVFYELAHQLPLPHNVSSHLDKASVM
  RLTISYLRVRKLLDAGDLDIEDDMKAQMNCFYLKALDGFVMVLTDDGDMIYISDNVNKY
  M GLTQFELTGHSVFDFTHPCDHEEMREMLTHRNGLVKKGKEQNTQRSFFLRMKCTLTSR
  GR TMNIKSATWKVLHCTGHIHVYDTNSNQPQCGYKKPPMTCLVLICEPIPHPSNIEIPL
  DSK TFLSRHSLDMKFSYCDERITELMGYEPEELLGRSIYEYYHALDSDHLTKTHHDMFT
  KGQV TTGQYRMLAKRGGYVWVETQATVIYNTKNSQPQCIVCVNYVVSGIIQHDLIFSLQ
  QTECV LKPVESSDMKMTQLFTKVESEDTSSLFDKLKKEPDALTLLAPAAGDTIISLDFG
  SNDTET DDQQLEEVPLYNDVMLPSPNEKLQNINLAMSPLPTAETPKPLRSSADPALNQE
  VALKLEP NPESLELSFTMPQIQDQTPSPSDGSTRQSSPEPNSPSEYCFYVDSDMVNEFK
  LELVEKLF AEDTEAKNPFSTQDTDLDLEMLAPYIPMDDDFQLRSFDQLSPLESSSASPE
  SASPQSTVT VFQQTQIQEPTANATTTTATTDELKTVTKDRMEDIKILIASPSPTHIHKE
  TTSATSSPYR DTQSRTASPNRAGKGVIEQTEKSHPRSPNVLSVALSQRTTVPEEELNPK
  ILALQNAQRKR KMEHDGSLFQAVGIGTLLQQPDDHAATTSLSWKRVKGCKSSEQNGMEQ
  KTIILIPSDLAC RLLGQSMDESGLPQLTSYDCEVNAPIQGSRNLLQGEELLRALDQVN
• Function: Functions as a master transcriptional regulator of theadaptive response to hypoxia .Under hypoxic conditions, activates the transcription of over 40 genes,including erythropoietin, glucose transporters, glycolytic enzymes,vascular endothelial growth factor, HILPDA, and other genes whoseprotein products increase oxygen delivery or facilitate metabolicadaptation to hypoxia . Plays an essentialrole in embryonic vascularization, tumor angiogenesis andpathophysiology of ischemic disease . Heterodimerizeswith ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' withinthe hypoxia response element of target gene promoters . Activation requires recruitment of transcriptionalcoactivators such as CREBBP and EP300 . Activity is enhanced by interaction with NCOA1 and/orNCOA2 . Interaction with redox regulatory proteinAPEX1 seems to activate CTAD and potentiates activation by NCOA1 andCREBBP . Involved in the axonaldistribution and transport of mitochondria in neurons during hypoxia. {ECO:0000250|UniProtKB:Q61221,ECO:0000269|PubMed:10202154, ECO:0000269|PubMed:10594042,ECO:0000269|PubMed:11292861, ECO:0000269|PubMed:11566883,ECO:0000269|PubMed:15465032, ECO:0000269|PubMed:16543236,ECO:0000269|PubMed:16973622, ECO:0000269|PubMed:17610843,ECO:0000269|PubMed:18658046, ECO:0000269|PubMed:19528298,ECO:0000269|PubMed:20624928, ECO:0000269|PubMed:22009797,ECO:0000269|PubMed:30125331, ECO:0000269|PubMed:9887100}.; Upon infection by human coronavirusSARS-CoV-2, is required for induction of glycolysis in monocytes andthe consequent pro-inflammatory state . In monocytes,induces expression of ACE2 and cytokines such as IL1B, TNF, IL6, andinterferons . Promotes human coronavirus SARS-CoV-2replication and monocyte inflammatory response .{ECO:0000269|PubMed:32697943}.
• Uniprot ID: HIF1A_HUMAN
• Ensembl ID: ENSG0000010064417
• HGNC ID: HGNC:4910

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Clinical Trial Drug(s) 1 drug(s) in total

AUY922

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Clear cell renal cell carcinoma [ICD-11: 2C90.Y] [1]

• Sensitive Disease: Clear cell renal cell carcinoma [ICD-11: 2C90.Y]
• Sensitive Drug: AUY922
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: HIF-1alpha/VEGFA/VEGFR signalling pathway; Regulation; N.A.
• In Vitro Model: ACHN cells; Pleural effusion; Homo sapiens (Human); CVCL_1067
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Our study is the first to identify that AUY922 can enhance the sensitivity of ccRCC to sunitinib. AUY922 not only has an inhibitory effect on ccRCC cells, but also enhances the inhibitory effect of sunitinib on ccRCC cells. Additionally, our research is the first to explore the mechanism of AUY922 in ccRCC, demonstrating that it targets the HIF-1/VEGFA/VEGFR pathway by inhibiting HSP90B1.

References

• Ref 1: AUY922 improves sensitivity to sunitinib in clear cell renal cell carcinoma based on network pharmacology and in vitro experiments. Heliyon. 2024 Jul 18;10(14):e34834.