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1 TRANSCRIPTION FACTOR NF- B: A NUCLEAR FACTOR IN B CELLS AND BEYOND. Fano, Centro di Biotecnologie 04 Aprile 2008 © Linda Palma, 2008 Università degli.

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Presentation on theme: "1 TRANSCRIPTION FACTOR NF- B: A NUCLEAR FACTOR IN B CELLS AND BEYOND. Fano, Centro di Biotecnologie 04 Aprile 2008 © Linda Palma, 2008 Università degli."— Presentation transcript:

1 1 TRANSCRIPTION FACTOR NF- B: A NUCLEAR FACTOR IN B CELLS AND BEYOND. Fano, Centro di Biotecnologie 04 Aprile 2008 © Linda Palma, 2008 Università degli Studi di Urbino

2 2 NF- B IDENTITY DOCUMENT NF- B REGULATION NF- B TARGET GENES NF- B FUNCTIONS NF- B AND CANCER NF- B AS THERAPEUTIC TARGET © Linda Palma, 2008 Università degli Studi di Urbino SUMMARY

3 3 © Linda Palma, 2008 Università degli Studi di Urbino GENE REGULATORY ELEMENTS

4 4 © Linda Palma, 2008 Università degli Studi di Urbino In early 80s, 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 LIGHT CHAIN GENE ENHANCER IN B CELLS DISCOVERING NF- B

5 5 © Linda Palma, 2008 Università degli Studi di Urbino

6 6 © Linda Palma, 2008 Università degli Studi di Urbino NF- B/Rel AND I B 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 I B proteins, the binding of which to the RHD interferes with the function of the NLS. All I Bs contain 6–7 ankyrin repeats, which mediate their binding to RHDs. Three family members, p65, cRel and RelB, contain transcriptional activation domains (TAD) at their C-terminus, and are therefore able to directly activate transcription.

7 7 © Linda Palma, 2008 Università degli Studi di Urbino THE NF- B ACTIVATION PATHWAY (1) Several stimuli are able to activate NF- B through the engagement of various cell-surface receptors:

8 8 © Linda Palma, 2008 Università degli Studi di Urbino THE NF- B ACTIVATION PATHWAY (2) Several adaptor proteins are recruited to the cytosolic domains of cell receptors upon their engagement: IRAKs RIP MALT Bcl10 TAB2/3

9 9 © Linda Palma, 2008 Università degli Studi di Urbino THE NF- B ACTIVATION PATHWAY (3) IRAKs RIP MALT Bcl10 TAB2/3 Transduction of extracellular stimuli converge on either of two intracellular signaling cascades, referred to as CLASSICAL NF- B ACTIVATION PATHWAY and ALTERNATIVE NF- B ACTIVATION PATHWAY

10 10 © Linda Palma, 2008 Università degli Studi di Urbino THE NF- B 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: IKK, catalytic IKK (NEMO), regulatory Homo- and heterodimers containing the IKK subunit are responsible of activation of the classical pathway, IKK homodimers are involved in the alternative pathway.

11 11 © Linda Palma, 2008 Università degli Studi di Urbino THE NF- B ACTIVATION PATHWAY (5) ALTERNATIVE ACTIVATION PATHWAY CLASSICAL ACTIVATION PATHWAY

12 12 © Linda Palma, 2008 Università degli Studi di Urbino NF- B 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 SEPS1 ABCA1 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) XIAP Activin 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-1 Adenovirus (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

13 13 © Linda Palma, 2008 Università degli Studi di Urbino Degeneration Redundancy Sequence-dimer pairs Exchange of dimers NF- B TARGET GENES (2) B MOTIF: 9-11 mer GGGRNNYYCC (R = purine; N = any nucleotide; Y = pyrimidine) CONSTITUTIVELY AND IMMEDIATELY ACCESSIBLE GENES (CIA) REGULATED LATE ACCESSIBILITY GENES (RLA) FINE TUNING OF TARGET GENE EXPRESSION RATES IN A CELL- AND STIMULUS- SPECIFIC MANNER

14 14 © Linda Palma, 2008 Università degli Studi di Urbino NF- B TARGET GENES (3) Growth factors, ligands and their modulators Transcription factors and Regulators Enzymes Cyclins Stress response genes Regulators of apoptosis Cytokines/Chemokinesytokines/Chemokines and their modulators Immunoreceptors Proteins involved in antigen presentation Cell adhesion molecules Acute phase proteins Viruses Early response genes NF- B proteins Cell-surface receptors IkBs A20

15 15 © Linda Palma, 2008 Università degli Studi di Urbino NF- B FUNCTIONS: APOPTOSIS (1) Fas / DR4 / DR5 FADD PROCASPASE 8 PROCASPASE 10 C-FLIP TRADD TRAF2 TRAF5 RIP1 TNFR1 / DR3 / DR6 / EDAR Death Receptors: APOPTOTIC RESPONSE NF- B FLIP c-IAP1 c-IAP2 XIAP Bcl-2 family members NF- B INDUCES GENES WHOSE FUNCTIONS INTERFERE WITH THOSE OF THE DEATH-INDUCING SIGNALING COMPLEXES

16 16 © Linda Palma, 2008 Università degli Studi di Urbino NF- B FUNCTIONS: APOPTOSIS (2) DEPOLARIZATION CASPASE-DEPENDENT AND –INDEPENDENT MECHANISMS Mitochondria: APOPTOTIC RESPONSE NF- B NF- B INDUCES GENES WITH ANTIOXIDANT FUNCTIONS REACTIVE OXYGEN SPECIES (ROS) glutathione-S-transferase Mn SOD Ferritin heavy chain Metallothionein

17 17 © Linda Palma, 2008 Università degli Studi di Urbino NF- B FUNCTIONS: APOPTOSIS (3) NF- B, 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.

18 18 © Linda Palma, 2008 Università degli Studi di Urbino NF- B FUNCTIONS: IMMUNITY (1) Bacteria and FungiBacteria 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 NF- B INDUCERS

19 19 © Linda Palma, 2008 Università degli Studi di Urbino NF- B FUNCTIONS: IMMUNITY (2) Pathogen INNATE IMMUNITY 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 ADAPTIVE IMMUNITY LYMPHOID ORGANS DEVELOPMENT, ANTIGEN PRESENTATION AND MAINTENANCE OF MEMORY CELLS APCs, T and B lymphocytes.

20 20 © Linda Palma, 2008 Università degli Studi di Urbino NF- B FUNCTIONS: IMMUNITY (3) NF- B Inflammatory genes mRNA Inflammatory genes mRNA

21 21 © Linda Palma, 2008 Università degli Studi di Urbino NF- B DYSFUNCTION (1) AgeingHeadaches Pain Complex Regional Pain Syndrome Cardiac Hypertrophy Muscular Dystrophy (type 2A) Muscle wasting Catabolic disorders Diabetes, Type 1Diabetes, Type 2 Obesity Fetal Growth Retardation Hypercholesterolemia AtherosclerosisHeart DiseaseChronic Heart Failure Ischemia/reperfusionStroke Cerebral aneurysm Angina Pectoris Pulmonary DiseaseCystic Fibrosis Acid-induced Lung Inury Pulmonary hypertension Chronic Obstructive Pulmonary Disease (COPD)Hyaline Membrane Disease Kidney Disease Glomerular Disease Alcoholic Liver Disease Leptospiriosis renal diseaseGut Diseases Peritoneal endometriosis Skin DiseaesNasal sinusitis Mesothelioma Anhidrotic Ecodermal Dysplasia-ID Behcet's Disease Incontinentia pigmentiTuberculosis AsthmaArthritisCrohn's DiseaseColitis (rat) Ocular Allergy Glaucoma Appendicitis Paget's Disease PancreatitisPeriodonitisEndometriosis Inflammatory Bowel Disease Inflammatory Lung isease SepsisSilica-inducedSleep apnoea AIDS (HIV-1)AutoimmunityAntiphospholipid Syndrome Lupus Lupus nephritis Waldenstrom macroglobulinemia Chronic Disease Syndrome Familial Mediterranean Fever Hereditary Periodic Fever syndrome Psychosocial stress diseases Neuropathological DiseasesFamilial amyloidotic polyneuropathy, inflamm neuropathy Traumatic brain injury Spinal cord injury Parkinson Disease Multiple Sclerosis Rheumatic Disease Alzheimers DiseaseAmyotropic lateral sclerosisHuntington's Disease Retinal Disease Cataracts Hearing loss Cancer

22 22 © Linda Palma, 2008 Università degli Studi di Urbino NF- B DYSFUNCTION (2) Cancer type Solid tumors (generally)BreastCervixOvary VulvaProstateKidneyBladder Lung Mesothelioma Non small-cell lung Liver PancreasEsophygeal/gastric Laryngeal Stomach ColonThyroidParathyroidMelanoma Endometrial (Uteris)Squamous cell carcinoma Head and neck Hilar Cholangiocarcinoma Oral carcinomaCylindromatosisBrooke-Spiegler, Trichoepithelioma Glioblastoma Hodgkins lymphomaAstrocytoma/glioblastomaNeuroblastoma Acute T-cell leukemia (+/-HTLV-1) Acute Non-lymphocytic leukemia Acute lymphoblastic leukemiaAcute myelogenous leukemiaMantle cell lymphoma Myelodysplastic syndrome Chronic lymphocytic leukemiaBurkitts Lymphoma (EBV)MALT lymphoma Multiple myelomaDiffuse large B-cell lymphoma

23 23 © Linda Palma, 2008 Università degli Studi di Urbino NF- B 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 INFLAMMATION IS INVOLVED IN TUMOR INITIATION, PROMOTION AND PROGRESSION 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-1 and IL-1RA and GASTRIC CANCER

24 24 © Linda Palma, 2008 Università degli Studi di Urbino NF- B AND CANCER (2) INADEQUATE PATHOGEN ERADICATION PROLONGED INFLAMMATORY SIGNALING DEFECTIVE ANTI-INFLAMMATORY MECHANISMS ENHANCED PROLIFERATION AND PROTECTION OF PRE-NEOPLASTIC / MALIGNANT CELLS FROM APOPTOSIS AND NECROSIS PERSISTENT NF- B ACTIVATION

25 25 © Linda Palma, 2008 Università degli Studi di Urbino NF- B 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 Chronic infection IL-8 / VEGF / MMPs Angiogenesis and metastases

26 26 © Linda Palma, 2008 Università degli Studi di Urbino NF- B AND CANCER (4)

27 27 © Linda Palma, 2008 Università degli Studi di Urbino NF- B AS TARGET FOR ANTICANCER DRUGS (1) MAJOR ISSUES: UPTAKE STABILITY EFFICACY IN PATIENTS SIDE EFFECTS

28 28 © Linda Palma, 2008 Università degli Studi di Urbino NF- B AS TARGET FOR ANTICANCER DRUGS (2)


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