lecture17

lecture17 - Some important human Transcription Factors...

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Unformatted text preview: Some important human Transcription Factors Inflammatory / Immune Responses Stat, NF-kB, AP-1, IRF Genotoxic Stress p53 Hormone / small molecule Responses Nuclear Hormone Receptors 1701 STAT Transcription Factors STAT dimer binds TTCCGGGAA activates many genes 1702 JAK-STAT Signaling Pathway 1703 STAT activation regulated via Tyr phosphorylation NFκB Transcription Factors structure-based recognition sequence (G)GGRN3-4(YCCN) Gouri Ghosh UCSD IκB-NFκB complex cannot bind DNA 1704 Many stimuli activate NF-κB TNF UV Virus IKK oxygen radicals IκB IL-1 Ltβ LPS Ag NF-κB NF-κB target genes suicide/survival inflammation growth/proliferation 1705 Control of the NF-κB/IκB signaling system IL-1 TNF LPS Ag UV Virus ubiquitin ligase P P IKK P P IκB NF-κB ub proteasome IκB NF-κB IκB NF-κB NF-κB target genes NF-κB 1706 The NF-κB family RelA/p65 RelA p50 p52 RelB cRel RelA Rel/cRel RelB p50 p52 p52 p50 cRel RelB NF-κB dimers IκB-family Ankyrin-Repeat domain Domain IκBα IκBβ IκBε NF-κB proteins are expressed specifically re. cell-type and stimulus so each cell contains different subsets of all possible dimers. 1707 The IκB-NFκB signaling module signaling module Iκ B NF- κ B cytoplasm nucleus IKK NF- κ B ε β α NF- κ B Three IkB proteins provide negative feedback to terminate NF-kB after stimulation. 1708 p53 - “the guardian of the genome” Mdm2 ubiquitin ligase human cancer cells: reveal which proteins are important for DNA damage response > 50% of human cancers show mutations in p53 1709 Nuclear Hormone receptors 1710 Nuclear Hormone Receptors 1711 Nuclear Hormone Receptors 3-4-5 rule 1712 Combinatorial possibilities due to heterodimerization 3 factors, 6 possible binding sites A specific inhibitor affects certain sites Lodish Fig. 11-23 1713 Combinatorial Control of Gene Expression Concept example 1: IFNβ enhancer example 2: Drosophila development Temporal Control p53 NFκB 1714 Combinatorial Control of Transcription a) Different TFs function together to activate a promoter. They function cooperatively, or synergistically. They synergize. b) A cell stimulus will activate multiple TFs. a) Different promoters require different subsets of TFs b) Different stimuli will activate distinct subsets of available TFs. 1715 Simple Control of Gene Expression Stimuli / Receptors R1 R2 R3 Kinases K1 K2 K3 Transcription Factors TF1 TF2 TF3 Gene Expression Programs G1 G2 G3 1716 Combinatorial Control of Gene Expression Receptors R1 R2 R3 R4 R5 R6 R7 Kinases K1 K2 K3 Transcription Factors TF1 TF2 TF3 Genes G1 G2 G3 G4 G5 G6 G7 1717 Combinatorial Control of Gene Expression Receptors R1 R2 R3 R4 R5 R6 R7 Kinases K1 K2 K3 Transcription Factors TF1 TF2 TF3 Genes G1 G2 G3 G4 G5 G6 G7 1718 Combinatorial Control of Gene Expression Receptors R1 R2 R3 R4 R5 R6 R7 Kinases K1 K2 K3 Transcription Factors TF1 TF2 TF3 Genes G1 G2 G3 G4 G5 G6 G7 1719 Sensing pathogen: innate immune signaling network LPS TNF IFNγ virus JNK IKK JAK TBK-1 IKKε/i AP-1 NF-kB IRF1 IRF3 Stats 1720 The interferon-beta enhancer: cooperative binding of several TF is required AP-1 IRF NF-kB p50 p65 AP-1 IRF The Enhanceosome NF-kB Tom Maniatis Dimitris Thanos 1721 IFNβ expression: combinatorial requirement IFNβ mRNA ChIP NFκB PIC HAT 1722 Protein-protein interactions between TFs are required transient transfection assay IRF NFκB AP-1 IFNβ mRNA ATF2195 binds to DNA and interacts with HMG I and NFkB ATF2192 binds to DNA but does not interact with either HMG or NFkB 1723 Nucleosome movement can be a rate limiting step a nucleosome over the INR needs to move downstream sliding assay SWI/SNF PIC IFNβslid = mutated promoter where the nucleosome is located downstream 1724 Nucleosome position imposes combinatorial TF requirement mRNA when nucleosome is already moved downstream only one TF is sufficient for activation 1725 Activation of Transcription on IFNβ promoter all TFs required one TF is sufficient Nucleosome movement Histone tail modifications PIC assembly promoter opening/initiation elongation 1726 Combinatorial Control of Transcription a) Different TFs function together to activate a promoter. They function cooperatively, or synergistically. They synergize. b) A cell stimulus will activate multiple TFs. a) Different promoters require different subsets of TFs b) Different stimuli will activate distinct subsets of available TFs. number of TFs = n number of combinations = specificity number of combinatorial code =n! 1727 Drosophila Development from egg to embryo: axis formation segmentation 1728 Drosophila Development: segmentation and cell identity 1729 Generating the body pattern 1. maternal effect genes: body axis 2. Segmentation genes: correct number of body segments 3. Homeotic Selector Genes: segment identity 1730 maternal effect genes generating a gradient reading the gradient 1731 A gradient allows expression of specific genes along the body axis to generate body segments 1732 Examples of Proteins localized within the multi-nucleated egg 1733 Specific combinations of activators and repressors on the eve promoter can produce very localized expression 1734 Combinations of TFs generate segment identity 1735 Mutations in the segmentation identity genes Normal antp mutant T3 to T2 1736 Similar segementation in mammalian development: same TFs are present and have similar functions 1737 ...
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This note was uploaded on 10/30/2010 for the course CHEM 114C taught by Professor Alexanderhoffmann during the Spring '08 term at UCSD.

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