1 / 28

TRANSCRIPTION FACTOR NF- k B: A NUCLEAR FACTOR IN B CELLS AND BEYOND.

TRANSCRIPTION FACTOR NF- k B: A NUCLEAR FACTOR IN B CELLS AND BEYOND. SUMMARY. ● NF- k B IDENTITY DOCUMENT ● NF- k B REGULATION ● NF- k B TARGET GENES ● NF- k B FUNCTIONS ● NF- k B AND CANCER ● NF- k B AS THERAPEUTIC TARGET. GENE REGULATORY ELEMENTS. DISCOVERING NF- k B.

tirza
Download Presentation

TRANSCRIPTION FACTOR NF- k B: A NUCLEAR FACTOR IN B CELLS AND BEYOND.

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. TRANSCRIPTION FACTOR NF-kB: A NUCLEAR FACTOR IN B CELLS AND BEYOND.

  2. SUMMARY ● NF-kB IDENTITY DOCUMENT ● NF-kB REGULATION ● NF-kB TARGET GENES ● NF-kB FUNCTIONS ● NF-kB AND CANCER ● NF-kB AS THERAPEUTIC TARGET

  3. GENE REGULATORY ELEMENTS

  4. DISCOVERING NF-kB In early 80’s, research studies on the mechanisms regulating gene transcription led these authors to the discovery of an apparently B cell-specific protein, able to bind to the kappa light polypeptide gene enhancer. They called it NUCLEAR FACTOR OF k LIGHT CHAIN GENE ENHANCER IN B CELLS

  5. NF-kB/Rel AND IkB FAMILIES OF PROTEINS The REL homology domain (RHD) mediates their dimerization and binding to DNA. The RHD also contains, at its carboxyl terminus, a nuclear localization signal (NLS) and is recognized by the IkB proteins, the binding of which to the RHD interferes with the function of the NLS. Three family members, p65, cRel and RelB, contain transcriptional activation domains (TAD) at their C-terminus, and are therefore able to directly activate transcription. All IkBs contain 6–7 ankyrin repeats, which mediate their binding to RHDs.

  6. THE NF-kB ACTIVATION PATHWAY (1) Several stimuli are able to activate NF-kB through the engagement of various cell-surface receptors:

  7. RIP RIP MALT IRAKs Bcl10 TAB2/3 THE NF-kB ACTIVATION PATHWAY (2) Several adaptor proteins are recruited to the cytosolic domains of cell receptors upon their engagement:

  8. RIP RIP MALT IRAKs Bcl10 TAB2/3 THE NF-kB ACTIVATION PATHWAY (3) Transduction of extracellular stimuli converge on either of two intracellular signaling cascades, referred to as CLASSICAL NF-kB ACTIVATION PATHWAY and ALTERNATIVE NF-kB ACTIVATION PATHWAY

  9. b b a a a b g g g g THE NF-kB ACTIVATION PATHWAY (4) The key regulator of both pathways is the Inhibitor of Kappa B Kinase (IKK), a high molecular weight complex (900 kDa) composed of three kinds of subunits: IKKa, catalytic IKKb, catalytic IKKg (NEMO), regulatory Homo- and heterodimers containing the IKKb subunit are responsible of activation of the classical pathway, IKKa homodimers are involved in the alternative pathway.

  10. THE NF-kB ACTIVATION PATHWAY (5) CLASSICAL ACTIVATION PATHWAY ALTERNATIVE ACTIVATION PATHWAY

  11. NF-kB TARGET GENES (1) BAFF *CXCL 11 IL-1b IL-13 *LIX (mouse) ENA-78 (CXCL5) and GCP-2 (CXCL6) *mob-1 BRL-1 CD40 *ICOS MHC Class I HLA-B7 TREM-1 Fibronectin Complement factor B CCL5 Eotaxin IL-1 *IL-15 Lymphotoxin a Neutrophil activating peptide-78 CCR5 CD48 IL-2 receptor a-chain b2 Microglobulin Complement B ICAM-1 Complement factor C4 CCL15/Leukotactin/ SCYA15 Fractalkine IL-2 IL-17 Lymphotoxin b RANTES CCR7 *IL-15 Lymphotoxin a Neutrophil activating peptide-78 CCR5 CD48 IL-2 receptor a-chain b2 Microglobulin Complement B ICAM-1 Complement factor C4 CCL15/Leukotactin/ SCYA15 Fractalkine IL-2 IL-17 Lymphotoxin b CCR7 CD83 Immunoglobulin Cgamma1 Nod2 Complement component 3 MadCAM-1 C-reactive protein CCL17 Gro alpha IL-6 IL-23A (p19) MCP-1/JE TCA3 T-cell activation gene 3 CXCR CD86 Immunoglobulin gamma1 Polymeric Ig receptor Complement Receptor 2 NCAM Hepcidin CCL19 Gro beta IL-8 IL-27 (p28) MIG TNFalpha CXCR2 CD98 Immunoglobulin gamma4 PGRP-S Proteasome Subunit LMP2 P-selectin Lipopolysaccharide binding protein CCL20 Gro gamma IL-9 EBI3/IL-27BMIP-1a,b TNFbeta CD137 CD134 Immunoglobulin e heavy chain T-cell receptor b chain Peptide Transporter TAP1 Tenascin-C Pentraxin PTX3 CCL22 Gro-1 IL-10 beta-Interferon   TRAIL (aka Apo2 ligand) CD154 *F11-receptor Immunoglobulin k light chain T-cell receptor/CD3gamma Tapasin VCAM-1 Serum amyloid A proteins (SAA1, SAA2, SAA3) CCL23/SYA23 *ICOS IL-11 IP-10 aka (LAG-1) TFF3 (Treefoil factor) CD3gamma FcRn Invariant Chain II TLR-2 DC-SIGN Angiotensinogen (Angiotensin II) Serum amyloid A proteins (SAA1, SAA2, SAA3) CCL28 IFN-g IL-12B (p40) KC MIP-2 VEGI CD21 Fc epsilon receptor II (CD23) Kinin B1 Receptor TLR9 ELAM-1 (CD62E, E-selectin) beta-defensin-2 Serum amyloid A proteins (SAA1, SAA2, SAA3) CINC-1 IL-1a IL-12A (p35) IiGp1 MIP-3alpha/CCL20 B7.1 (CD80) CD38 HLA-G MHC class I (H-2Kb) *TNF-Receptor p75/80 (CD120B) Endoglin C4b binding protein Tissue factor-1*CYP2E1 CYP2C11 CYP7b COX-2 Ferritin H chain HSP90-alpha *5-Lipoxygenase (guinea pig) 12-Lipoxygenase Inducible NO-Synthase *MAP4K1   Cu/Zn SOD SOD1 SOD2 *Mx1 NAD(P)H quinone oxidoreductase (DT-diaphorase) Phospholipase A2 SEPS1ABCA1 ABCC6 A1 adenosine receptor A2A *ADAM19 Amiloride-sensitive sodium channel *alpha2B-adrenergic receptor Bradykinin B1-Receptor *CD23 CD69 DOR Epidermal Growth Factor Receptor ErbB2 Gal1 Receptor Lox-1 Ly49 Mdr1 Mu-opioid receptor mGlu2 Neuropeptide Y-Y1 receptor *NMDA receptor subunit 2A (rat) *NMDA receptor subunit NR-1 (GRIN1 gene) Oxytocin receptor PAF receptor 1 P-gp RAGE- receptor ASC Bax Bfl1/A1 Bcl-xL Bcl-2 B7-H1 BNIP3 Caspase-11 Nr13 c-FLIP CD95 (Fas) *Fas-associated phosphatase-1 Fas-Ligand IAPs IEX-1L TRAF-1 TRAF-2 *TRAF-2 binding protein (Carp) XIAPActivin A Angiopoietin BCAP BDNF BLyS BLNK BMP-2 BMP-4 CGRP FGF8 FLRG G-CSF GM-CSF *HGF/SF EPO *IGFBP-1 IGFBP-2 M-CSF (CSF-1) Midkine (neurite growth promoting factor-2) NGF NK-1R NK4 Nrg1 OPN PDGF B chain PlGF Proenkephalin Prolactin Stem Cell Factor *Thrombospondin-1 (TSP-1) *Thrombospondin-2 (THBS2) VEGF C *WNT10B*B94 *Egr-1 p22/PRG1 *p62 *TIEG A20 ABIN-3 Androgen receptor Bcl-3 BMI-1 CDX1 *c-fos (fish gene) c-myb c-myc c-rel C/EBPdelta *DC-SCRIPT Dmp1 E2F3a Elf3 *ELYS *ETR101 Gata-3 *Glucocorticoid receptor HIF-1alpha HOXA9 IRF-1 IRF-2 IRF-4 IRF-7 IkB-a IkB-e junB jmjD3 Lef1 LZIP Mail nfkb2 nfkb1 NLRP2 NURR1 Osterix p53 Progesterone receptor relb Snail Sox9 Stat5a Tfec Twist WT1 YY1 · *ABC Transporters   *N-acetylglucosaminyltransferase I (rat gene)   ADH   AID   AMACR   ARF-related protein-1   Argininosuccinate synthetase   Aromatase (promoter II)   ART2.1   alpha 1ACT   BACE-1 Btk Cathepsin B *Cathepsin L *Ceramide glycosyltransferase Chitinase 3-like protein *cis-retinoid/androgen dehydrogenase type 1 (CRAD1) *cis-retinoid/androgen dehydrogenase type 2 (CRAD2) Collagenase 1 *Dihydrodiol dehydrogenase *DYPD DNASIL2 EL *ENO2 *GAD67 GD3-synthase gp91 phox Gelatinase B GSTP1-1 Glutamate-cysteine ligase  GCLC *Glutamate-cysteine ligase modifier *gamma glutamylcysteine synthetase *Glucose l-6-phosphate dehydrogenase Glucose-6-phosphatase GnRH II Granzyme B *Soluble Guanylyl cyclase alpha (1)   *Heparanase  HO-1 Hyaluronan synthase 11bHSD2 *17bHSD H+-K+ATPase alpha2 Iodothyronine deiodinase (type 2) Lipocalin-type prostaglandin D synthase (L-PGDS) Lysozyme Mthfr *MKP-1 MMP-3 matrix metalloproteinaase-3 MMP-9 matrix metalloproteinaase-9 MLCK iNOS n-NOS *PDE7A1 PIM-1 Plk3 PIK3CA *PP5 PKCdelta PLCdelta 1 *PTGIS prostaglandin synthase *PGES prostaglandin E synthase PTP1B PTHrP RACK1 *REV3 Slfn-2 Serpin 2A SIAT1 SNARK SSAT *SUV3 TERT Transglutaminase TTG Type II-secreted phospholipase A2 Uridine phosphorylase *Xanthine Dehydrogenase*ABCG5 (bovine) ABCG8 (bovine) AbetaH-J-J alpha-1 acid glycoprotein alpha-fetoprotein AMH *beta-amyloid APOBEC2 Apolipoprotein C III Apolipoprotein D Apolipoprotein E AQP4 *Biglycan BRCA2 Calsarcin-1 *Caveolin-1 *Clone 330 *Clone 156 *Clone 68 *p21-CIP1 *Claudin-2 a2(I) collagen *Connexin32 Cyclin D1 Cyclin D2 *Cyclin D3 DIF2 DMT1 Elafin Endothelin 1 Ephrin-A1 Factor VIII Ferritin Heavy Chain Gadd45beta Galpha i2 *GIF Galectin 3 GBP-1 epsilon-Globin zeta-Globin *GS3686 Hair K5 keratin *HCCS1 HMG14 IBABP IMP2 K3 Keratin K6b Keratin K15 Keratin *Lactoferrin Laminin B2 Chain Lipocalin-2 Mts1 Mir125b Mir146a, b Mir155 MNE1 Mucin (MUC-2) Myelin basic protein MCT1 Naf1 Neutrophil gelatinase-associated lipocalin NLF1 *p11 PA28 alpha PA28 beta PAI-1 *Pax8 *PCBD Perforin *PGK1 POMC Pregnancy-specific glycoprotein rnCGM3 Prodynorphin Prostate-specific antigen PTEN RAG-1 RAG-2 RbAp48 *RICK SerpinE2 S100A6 (calcyclin) SH3BGRL SK2 channels Skp2 *Spergen-1 SWS1 Syncytin-1 Syndecan-4 TAUT TASK-2 *Tissue factor pathway inhibitor-2 (TFPI-2) *Transferrin (mosquito) TRIF TRPC1 *UBE2M *UCP-2 Uroplakin Ib 25-hydroxyvtamin D3 1alpha hydroxylase Vimentin a1-antitrypsin Gro-1Adenovirus (E3 region) Avian Leukosis Virus Bovine Leukemia Virus CMV EBV (Wp promoter) HBV (pregenomic promoter) HIV-1 HSV (ICP90, ICPO) JC Virus HPV type 16 SIV SV-40

  12. NF-kB TARGET GENES (2) kB MOTIF: 9-11 mer GGGRNNYYCC (R = purine; N = any nucleotide; Y = pyrimidine) ● CONSTITUTIVELY AND IMMEDIATELY ACCESSIBLE GENES (CIA) ● REGULATED LATE ACCESSIBILITY GENES (RLA) ● Degeneration ● Redundancy ● Sequence-dimer pairs ● Exchange of dimers FINE TUNING OF TARGET GENE EXPRESSION RATES IN A CELL- AND STIMULUS- SPECIFIC MANNER

  13. NF-kB TARGET GENES (3) ● Growth factors, ligands and their modulators ● Transcription factors and Regulators ● Enzymes ● Cyclins ● Cytokines/Chemokines and their modulators ● Immunoreceptors ● Proteins involved in antigen presentation ● Cell adhesion molecules ● Acute phase proteins ● Stress response genes ● Regulators of apoptosis ● IkBs ● A20 ● Viruses ● Early response genes ●NF-kB proteins ● Cell-surface receptors

  14. NF-kB FUNCTIONS: APOPTOSIS (1) ● Death Receptors: NF-kB Fas / DR4 / DR5 TNFR1 / DR3 / DR6 / EDAR FLIP c-IAP1 c-IAP2 XIAP Bcl-2 family members FADD PROCASPASE 8 PROCASPASE 10 C-FLIP TRADD TRAF2 TRAF5 RIP1 APOPTOTIC RESPONSE NF-kB INDUCES GENES WHOSE FUNCTIONS INTERFERE WITH THOSE OF THE DEATH-INDUCING SIGNALING COMPLEXES

  15. NF-kB FUNCTIONS: APOPTOSIS (2) ● Mitochondria: CASPASE-DEPENDENT AND –INDEPENDENT MECHANISMS NF-kB DEPOLARIZATION glutathione-S-transferase Mn SOD Ferritin heavy chain Metallothionein REACTIVE OXYGEN SPECIES (ROS) NF-kB INDUCES GENES WITH ANTIOXIDANT FUNCTIONS APOPTOTIC RESPONSE

  16. NF-kB FUNCTIONS: APOPTOSIS (3) NF-kB, some members of its activation pathway and some of its target gene products are themselves substrates of caspases. The ratio between pro-apoptotic and anti-apoptotic activities can target a given cell type to life or death in response to various stimuli.

  17. NF-kB FUNCTIONS: IMMUNITY (1) NF-kB INDUCERS Bacteria and Fungi Bacterial or Fungal Products Viruses Viral Products Eukaryotic parasite (Inflammatory) Cytokines Physiological (Stress) Conditions Physical Stress Oxidative Stress Environmental Hazards Therapeutically used drugs Modified Proteins Overexpressed Proteins Receptor Ligands Apoptotic Mediators Mitogens, Growth Factors and Hormones  Physiological Mediators  Chemical Agents

  18. NF-kB FUNCTIONS: IMMUNITY (2) Pathogen INNATE IMMUNITY INFLAMMATION AND COMPLEMENT CASCADE Epithelial cells from lung, liver and intestinal mucosa and professional immune cells (macrophages, neutrophils, dendritic cells, mast cells, eosinophils, basophils and natural killer cells). ADAPTIVE IMMUNITY LYMPHOID ORGANS DEVELOPMENT, ANTIGEN PRESENTATION AND MAINTENANCE OF MEMORY CELLS APCs, T and B lymphocytes.

  19. NF-kB NF-kB Inflammatory genes Inflammatory genes mRNA mRNA NF-kB FUNCTIONS: IMMUNITY (3)

  20. NF-kB DYSFUNCTION (1)

  21. NF-kB DYSFUNCTION (2) Cancer type

  22. NF-kB AND CANCER (1) Epidemiological data have led to hypothesize an association between INFLAMMATION and CANCER. Examples: silica / asbestos / cigarette smoke and LUNG CANCER H. pylori infection and GASTRIC CANCER IBDs and COLON CANCER HPV and CERVICAL CANCER EBV and BURKITT LYMPHOMA viral hepatitis and LIVER CANCER Genetic data exist, linking polymorphisms of PRRs genes and other inflammatory genes to increased cancer risk. Examples: TLR6 and TLR10 and PROSTATE CANCER NOD2 locus and COLORECTAL CANCER IL-1b and IL-1RA and GASTRIC CANCER INFLAMMATION IS INVOLVED IN TUMOR INITIATION, PROMOTION AND PROGRESSION

  23. NF-kB AND CANCER (2) ● INADEQUATE PATHOGEN ERADICATION ●PROLONGED INFLAMMATORY SIGNALING ●DEFECTIVE ANTI-INFLAMMATORY MECHANISMS PERSISTENT NF-kB ACTIVATION ENHANCED PROLIFERATION AND PROTECTION OF PRE-NEOPLASTIC / MALIGNANT CELLS FROM APOPTOSIS AND NECROSIS

  24. Chronic infection IL-8 / VEGF / MMPs Angiogenesis and metastases NF-kB AND CANCER (3) Tumorigenesis requires six essential alterations to normal cell physiology: ● self-sufficiency in growth signals ● insensitivity to growth inhibition ● evasion of apoptosis ● immortalization ● sustained angiogenesis ● tissue invasion and metastasis

  25. NF-kB AND CANCER (4)

  26. NF-kB AS TARGET FOR ANTICANCER DRUGS (1) MAJOR ISSUES: ● UPTAKE ● STABILITY ● EFFICACY IN PATIENTS ● SIDE EFFECTS

  27. NF-kB AS TARGET FOR ANTICANCER DRUGS (2)

More Related