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Transcription Factors

Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s P rogrammes at the University of Pécs and at the University of Debrecen Identification number : TÁMOP-4.1.2-08/1/A-2009-0011.

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Transcription Factors

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  1. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat theUniversity of Pécs and at the University of Debrecen Identificationnumber: TÁMOP-4.1.2-08/1/A-2009-0011

  2. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat theUniversity of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011 Tímea Berki and Ferenc Boldizsár Signaltransduction TranscriptionFactors

  3. Structuralgroups of transcriptionfactors • Helix-loop-helixeg. MyoD, c-Myc • Leucin zippers eg. AP-1, CREB • Zinc-coordinating DNA-binding domains eg. Zinc fingers: nuclear receptors for steroids, thyroid hormone; GATA factors • Helix-turn-helixeg. Homeobox; Forkhead / winged helix • Beta-scaffoldfactors with minorgroovecontactseg. NFkB, NFAT, STAT, p53 • Others

  4. Structuralgroups of transcriptionfactors Zincfingertranscriptionfactors Basic helix-loop-helix Helix Helix Loop Loop Zn Zn Helix Helix C H C H DNA binding Transactivation Transactivation C H C H Basic leucinezipper DNA-binding domain DNA-binding domain NH2 H2N

  5. Functionaldomains of transcriptionfactors Transactivation Dimerization Hinge region C-terminal domain N-terminal domain F A/B C D E Ligand binding domain (LBD) DNA binding domain (DBD) Ligand

  6. Nuclear receptor superfamily GR GR Steroid Recetors RXR Heterodimers GR MR PR AR T3R RAR VDR PPAR PPAR EcR FXR CAR LXR PXR/SXR Glucocorticoid Mineralocorticoid Progesterone Androgen Thyroidhormone All-trans RA 1,2,5-(OH)2-VD Fattyacids 15d-12,14-PGJ Ecdysone Bileacids Androstane Oxysterol Xenobiotics RXR R DimericOrphanReceptors Monomeric/TetheredOrphanReceptors RXR COUP HNF-4 TR2 TLX GCNF 9-cis RA NGFI-B SF-1 Rev-erb ROR ERR RXR RXR RXR

  7. Mechanism of steroid receptor action Hormone Plasma membrane Cytoplasm HSP HSP RXR RXR GR GR GR GR GR RXR RXR R R GR Nucleus Co-repressor Co-activator Co-activator RNA polymerase RNA polymerase Co-repressor Co-activator Co-activator Co-activator RNA polymerase RNA polymerase RNA polymerase Transcription Transcription Transcription HRE HRE HRE HRE

  8. Functionalgroups of TFs • General transcription factors: constitutively active, present in all cells at all times, bind TATA box, form preinitiation complex eg. TFIIA-H • Specific transcription factors /upstream transcription factors are conditionally active • Developmental (cell specific) eg. GATA, MyoD, Hox,Winged helix • Signal-dependent

  9. Signal-dependentTFs • Extracellularligand(eg. nuclear receptors) • Intracellularligand(eg. SREBP, p53) • Cell-membrane receptor dependent • Resident nuclear (eg. CREB, AP-1, Mef-2) • Latentcytoplasmic(eg. STAT, NFAT, NFkB, Notch)

  10. TFsin T cellactivationinducecytokineproduction a b z z d e e g TCR CD28 CD3 Plasmamembrane DAG GRB2 ZAP70 SOS RAS GTP RAS GRP1 FOS JUN Calcium flux, NFAT activation MAPK activation, AP1 formation AP1 Nucleus IL-12 NFAT

  11. Structure of STATs P Y NH2 Coiled coil DBD Lk SH2 TAD 0 200 400 600 800

  12. Regulation of transcription Post-transcriptionalcontrol MicroRNAs, alternativesplicing, alternativepolyadenylation, RNA-bindingproteins, etc. miRNAs TF TF mRNAs Transcriptionalcontrol Transcriptionfactors, chromatinstate, combinatorialcontrol, co-factors, alternativepromoters, etc.

  13. Mechanism of generegulation • General transcription factors and the RNA Polymerase interacts with numerous coregulators (specific transcription factors) • Activators bind to enhancer elements • Repressors bind to silencer elements of the DNA upstream from the TATA box

  14. GrowthfactorinducedTFs and theirbiologicaleffect HER2 GRB2 SOS CDC42 Rac Ras Rho ERK pathway JNK pathway p38 pathway Raf MEKK Tak PI3K MKK4/7 MKK3/6 MEK1/2 Akt Erk JNK p38 mTor Cellsurvival Proliferation Apoptosisresistance Metastasis Angiogenesis

  15. Someimportanttranscriptionfactors

  16. Transcriptionfactors and diseases • IPEXsyndrome (ImmunodysregulationPolyendocrinopathyEnteritisX-linked), “Scurfy” phenotype in mouse: FoxP3 • Rett-syndrome: MECP2 • Li-Fraumeni-syndrome: p53

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