Molecule Information

General Information of the Molecule (ID: Mol04036)
Name
Hypoxia-inducible factor 1-alpha (HIF-1alpha) ,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
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Molecule Type
Protein
Gene Name
HIF1A
Gene ID
3091
Location
chr14:61695513-61748259[+]
Sequence
MEGAGGANDKKKISSERRKEKSRDAARSRRSKESEVFYELAHQLPLPHNVSSHLDKASVM
RLTISYLRVRKLLDAGDLDIEDDMKAQMNCFYLKALDGFVMVLTDDGDMIYISDNVNKYM
GLTQFELTGHSVFDFTHPCDHEEMREMLTHRNGLVKKGKEQNTQRSFFLRMKCTLTSRGR
TMNIKSATWKVLHCTGHIHVYDTNSNQPQCGYKKPPMTCLVLICEPIPHPSNIEIPLDSK
TFLSRHSLDMKFSYCDERITELMGYEPEELLGRSIYEYYHALDSDHLTKTHHDMFTKGQV
TTGQYRMLAKRGGYVWVETQATVIYNTKNSQPQCIVCVNYVVSGIIQHDLIFSLQQTECV
LKPVESSDMKMTQLFTKVESEDTSSLFDKLKKEPDALTLLAPAAGDTIISLDFGSNDTET
DDQQLEEVPLYNDVMLPSPNEKLQNINLAMSPLPTAETPKPLRSSADPALNQEVALKLEP
NPESLELSFTMPQIQDQTPSPSDGSTRQSSPEPNSPSEYCFYVDSDMVNEFKLELVEKLF
AEDTEAKNPFSTQDTDLDLEMLAPYIPMDDDFQLRSFDQLSPLESSSASPESASPQSTVT
VFQQTQIQEPTANATTTTATTDELKTVTKDRMEDIKILIASPSPTHIHKETTSATSSPYR
DTQSRTASPNRAGKGVIEQTEKSHPRSPNVLSVALSQRTTVPEEELNPKILALQNAQRKR
KMEHDGSLFQAVGIGTLLQQPDDHAATTSLSWKRVKGCKSSEQNGMEQKTIILIPSDLAC
RLLGQSMDESGLPQLTSYDCEVNAPIQGSRNLLQGEELLRALDQVN
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3D-structure
PDB ID
7LVS
Classification
Transcription
Method
X-ray diffraction
Resolution
2.02  Å
Function
Functions as a master transcriptional regulator of the adaptive response to hypoxia (PubMed:11292861, PubMed:11566883, PubMed:15465032, PubMed:16973622, PubMed:17610843, PubMed:18658046, PubMed:20624928, PubMed:22009797, PubMed:30125331, PubMed:9887100). Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor, HILPDA, and other genes whose protein products increase oxygen delivery or facilitate metabolic adaptation to hypoxia (PubMed:11292861, PubMed:11566883, PubMed:15465032, PubMed:16973622, PubMed:17610843, PubMed:20624928, PubMed:22009797, PubMed:30125331, PubMed:9887100). Plays an essential role in embryonic vascularization, tumor angiogenesis and pathophysiology of ischemic disease (PubMed:22009797). Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters (By similarity). Activation requires recruitment of transcriptional coactivators such as CREBBP and EP300 (PubMed:16543236, PubMed:9887100). Activity is enhanced by interaction with NCOA1 and/or NCOA2 (PubMed:10594042). Interaction with redox regulatory protein APEX1 seems to activate CTAD and potentiates activation by NCOA1 and CREBBP (PubMed:10202154, PubMed:10594042). Involved in the axonal distribution and transport of mitochondria in neurons during hypoxia (PubMed:19528298). .; (Microbial infection) Upon infection by human coronavirus SARS-CoV-2, is required for induction of glycolysis in monocytes and the consequent pro-inflammatory state (PubMed:32697943). In monocytes, induces expression of ACE2 and cytokines such as IL1B, TNF, IL6, and interferons (PubMed:32697943). Promotes human coronavirus SARS-CoV-2 replication and monocyte inflammatory response (PubMed:32697943). .
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Uniprot ID
HIF1A_HUMAN
Ensembl ID
ENSG00000100644
HGNC ID
HGNC:4910
        Click to Show/Hide the Complete Species Lineage
Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens
Type(s) of Resistant Mechanism of This Molecule
  MRAP: Metabolic Reprogramming via Altered Pathways
Drug Resistance Data Categorized by Drug
Approved Drug(s)
2 drug(s) in total
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Etoposide
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Metabolic Reprogramming via Altered Pathways (MRAP) Click to Show/Hide
Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [1]
Metabolic Type Redox metabolism
Resistant Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Resistant Drug Etoposide
 Drug Info 
Molecule Alteration Activity
activation
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
H1299 cells Lung Homo sapiens (Human) CVCL_0060
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Here we showed that exposure to chemotherapeutic drug etoposide induces an exacerbation of ROS production which activates HIF-1-mediated the metabolic reprogramming toward increased glycolysis and lactate production in non-small cell lung cancer.
Fluorouracil
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Metabolic Reprogramming via Altered Pathways (MRAP) Click to Show/Hide
Disease Class: Colorectal cancer [ICD-11: 2B91.1] [2]
Metabolic Type Glucose metabolism
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Resistant Drug Fluorouracil
 Drug Info 
Molecule Alteration Expression
Up-regulation
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Longevity regulating pathway - multiple species Activation hsa04213
Breast cancer Activation hsa05224
Wnt signaling pathway Activation hsa04310
Adherens junction Activation hsa04520
In Vitro Model Caco2 cells Colon Homo sapiens (Human) CVCL_0025
DLD-1 cells Colon Homo sapiens (Human) CVCL_0248
DiFi cells Colon Homo sapiens (Human) CVCL_6895
HCT-116 cells Colon Homo sapiens (Human) CVCL_0291
HCT15 cells Colon Homo sapiens (Human) CVCL_0292
HCT8 cells Colon Homo sapiens (Human) CVCL_2478
HT-29 cells Colon Homo sapiens (Human) CVCL_0320
LOVO cells Colon Homo sapiens (Human) CVCL_0399
SW1116 cells Colon Homo sapiens (Human) CVCL_0544
SW-480 cells Colon Homo sapiens (Human) CVCL_0546
T84 cells Colon Homo sapiens (Human) CVCL_0555
Experiment for
Molecule Alteration		 qRT-PCR; Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description Upregulation of HIF-1alpha in 5-FU-resistant CRC occurred through non-oxygen-dependent mechanisms of reactive oxygen species-mediated activation of PI3K/Akt signaling and aberrant activation of beta-catenin in the nucleus. Both HIF-1alpha gene knock-down and pharmacological inhibition restored the sensitivity of CRC to 5-FU.
References
Ref 1 Lactate-induced MRP1 expression contributes to metabolism-based etoposide resistance in non-small cell lung cancer cells. Cell Commun Signal. 2020 Oct 23;18(1):167.
Ref 2 ROS/PI3K/Akt and Wnt/beta-catenin signalings activate HIF-1alpha-induced metabolic reprogramming to impart 5-fluorouracil resistance in colorectal cancer. J Exp Clin Cancer Res. 2022 Jan 8;41(1):15.

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