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DBD

DBD. bHLH transcription factors: HIF-1, AHR. HIF-1 Hypoxia inducible factor. oxidative stress. hypoxia. O 2 concentration. O 2 consumption (oxidative phosphorylation). O 2 delivery (tissue capillaries). O 2 homeostasis. changes in O 2 homeostasis. cardiac diseases.

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DBD

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  1. DBD

  2. bHLH transcription factors: HIF-1, AHR

  3. HIF-1 Hypoxia inducible factor

  4. oxidative stress hypoxia O2 concentration O2 consumption (oxidative phosphorylation) O2 delivery (tissue capillaries) O2 homeostasis

  5. changes in O2 homeostasis cardiac diseases malignant tumours cerebrovascular diseases chronic pulmonar diseases „global” regulator: hypoxia inducible factor 1 HIF-1

  6. HIF - 1 basic helix - loop - helix (bHLH) protein eukaryote transcription factor super gene family

  7. Heterodimer bHLH proteins I class subunit ARNT (aryl hydrocarbon receptor nuclear translocator) HIF - 1 ARNT 2 ARNT 3 (MOP 3) MOP 9 II class subunit AHR (aryl hydrocarbon receptor) CLOCK HIF - 1  HIF - 2  (EPAS 1, HLF, HRF, MOP 2) HIF - 3  NPAS 1 (MOP 5) NPAS 2 (MOP 4) SIM 1 SIM 2

  8. Heterodimer bHLH proteins I class subunit ARNT (aryl hydrocarbon receptor nuclear translocator) HIF - 1 ARNT 2 ARNT 3 (MOP 3) MOP 9 II class subunit AHR (aryl hydrocarbon receptor) CLOCK HIF - 1  HIF - 2  (EPAS 1, HLF, HRF, MOP 2) HIF - 3  NPAS 1 (MOP 5) NPAS 2 (MOP 4) SIM 1 SIM 2 HIF - 1: HIF -1  / HIF - 1  heterodimer in every human tissues

  9. bHLH domain: DNA binding dimerisation PAS (PER, ARNT, SIM) domain: substrate binding dimerisation transactivation HIF - 1 basic helix - loop - helix (bHLH) protein eukaryote transcription factor super gene family

  10. 5’ - RCGTG - 3’ + other TF binding site HIF - 1 HNF 4 (hepatocyte nuclear factor 4) CBP (CREB binding protein) p53 p300 SRC - 1 TIF 2 oxygen concentration redox status + ? Binding of HIF- 1 to DNA HRE: hypoxia response element

  11. expression of O2 sensitive genes hypoxia HIF - 1  O2 sensor HIF - 1  HIF - 1  dimer formation increase normoxia HIF - 1  hypoxia signaling

  12. Formation of HIF-1 heterodimer is dependent on O2 dependent degradation of HIF-1 expression of O2 sensitive genes HIF - 1  HIF - 1  hypoxia HIF - 1  HIF - 1  normoxia degradation

  13. HIF-1signaling VHL von Hippel-Lindau tumor szupresszor fehérje VHL VHL proteolysis HO HIF - 1  HO ubi expression of O2 sensitive genes HIF - 1  HIF - 1  hypoxia HIF - 1  HIF - 1  O2 normoxia Pro hydroxylase Asn hydroxylase HO HIF - 1  HO

  14. hypoxia signaling, expression of O2 sensitive genes ~ 70 genes directly 1% of the human genome indirectly vascular tone and O2 delivery: erythropoetin VEGF (vascular endothelial growth factor) VEGF receptor FLT - 1 NO synthase 2 glucose metabolism and transport: hexokinase lactate dehydrogenase pyruvate kinase GLUT 1 GLUT 3

  15. Module 4: Figure HIF functions Cell Signalling Biology www.cellsignallingbiology.org 2007

  16. AHR Aryl hydrocarbon receptor

  17. Heterodimer bHLH proteins I class subunit ARNT (aryl hydrocarbon receptor nuclear translocator) HIF - 1 ARNT 2 ARNT 3 (MOP 3) MOP 9 II class subunit AHR (aryl hydrocarbon receptor) CLOCK HIF - 1  HIF - 2  (EPAS 1, HLF, HRF, MOP 2) HIF - 3  NPAS 1 (MOP 5) NPAS 2 (MOP 4) SIM 1 SIM 2

  18. polyaromatic hydrocarbons (PAH) hydrocarbon molecules made of multiple benzene rings products of incomplete combustion co-planar, lipophilic, unreactive readily metabolized by P450 enzymes many PAH compounds are genotoxic halogenated PAH (HPAH) PAH with substituent halogen atoms (chlorine, bromine, etc.) rings connected by intervening dioxin ring, furan ring, C-C bond (PCBs) co-planar, lipophilic, unreactive often resist Phase-1 metabolism by P450 enzymes many HPAH are endocrine disruptor chemicals (EDCs) Nuclear receptor mediated toxicity -P450 enzyme induction by dioxins and PCBs HLTH 340 Lecture B6

  19. dioxin (TCDD) first discovered as trace contaminant in defoliant herbicide 2,4,5-T used to defoliate trees in VN TCDD toxic by-product created in production TCDD is potent teratogenic agent birth-defects and spontaneous abortions in exposed VN civilians (2.1 million directly) anencephaly, cleft palate, spinal bifida interferes with regulatory control of embryo CNS and head development disrupts retinoid hormone systems (vit.A) also abnormal reproductive function acts as EDC by antiestrogen effects excessive rate of estrogen degradation non-genotoxic (epigenetic) carcinogen does not react with DNA (not mutagen) disrupts normal cell regulation Dioxin contamination of 2,4,5-T herbicide (Agent Orange) in Vietnam war (1964-73) HLTH 340 Lecture B6

  20. AhR aryl hydrocarbon receptor protein binds PAH or HPAH xenobiotics as ligands HSP90 heat-shock protein chaperone protein acts as stabilizer of AhR ARNT AhR nuclear transporter protein forms heterodimer complex with AhR complex binds to DREs Genetic induction of CYP 1A1 via transcriptional activation by the ligand/AhR/ARNT complex XRE= xenobiotic response element DRE = dioxin response element HLTH 340 Lecture B6

  21. „Ah gene battery” Nqo1: NAD(P)H:quinone oxidoreductase Aldh3a1: cytoplasmic aldehyde-dehydrogenase 3 Ugt1a6: UDP-glucuronosyltransferase 1A6 Gsta1: glutathione-transferase

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