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Génátírás szabályozása: transzkripciós mechanizmusok

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1 Génátírás szabályozása: transzkripciós mechanizmusok
cikk-referáló Génátírás szabályozása: transzkripciós mechanizmusok Dr. Marcsek Zoltán

2 Génexpresszió fenotípus DNA in cell mRNA protein
Courtesy The Protein Society fenotípus

3

4 eukaryoták promóter elemei
a promóter elemei többé-kevésbé jól definiáltak a transzkripció start helyétől különböző távolságra vannak gyakran hiányzik általában van

5 egy tipikus promóter

6 az eukaryota transzkripció szabályozása

7 szabályozás transzkripciós faktorokkal
egy transzkripciós faktor (vagy transzkripciós faktorok egy csoportja) egy géncsoport expresszióját szabályozhatja (pl. heat shock fehérjék, G1/S restrikciós pont fehérjék, stb) egy gén átírását egy vagy több, egymástól független transzkripciós faktor szabályozhatja (pl. metallothionine) magas expresszió kiváltásához gyakran több, különböző 'response' elemhez kötő transzkripciós faktor lehet szükséges

8 Nuclear Factor-κB: A Holy Grail in Cancer Prevention and Therapy
Bharat B. Aggarwal, Gautam Sethi, Asha Nair, Haruyo Ichikawa Cytokine Res. Lab, Dept. Exp. Therapeutics, Univ. Texas M.D. Anderson Cancer Center, Houston, Tx ’invited review’ Current Signal Transduction and Therapeutics 2006.

9 transzkripciós faktor
NFkB mi az, mit csinál, miért jó, ha ismerjük? transzkripciós faktor

10 NFkB Baltimore & Sen fedezték fel mint egy B-sejt-specifikus magi proteint amely az immunoglobulin k könnyű láncának meghatározott szekvenciájához kötődik és a gén átírását serkenti (enhancer) (Cell 47: , 1986) az NFkB a Rel transzkripciós faktor családba tartozik amely nagyszámú, az immunválasszal, a gyulladással, a sejtosztódással és apoptózissal összefüggő gén expresszióját szabályozza az emlős sejtekben öt eltérő NFkB (rel) alegységet ismerünk amelyek kb. 300 nagyon konzervált aminosat tartalmaznak a citoplazmában az NFkB inaktív formában több, különböző kombinációban található (heterodimer p50/p65 (Rel A) és az inhibítor IkBa alegység)

11 Family of NFkB and Inhibitory kB (IkB) proteins
Nat.Rev.Cancer 2: , 2002

12 p105 (contains p50 NFkB1) Name: p105 (contains p50 subunit, a.k.a. NFkB1) Descr: Once in the nucleus initiates transcription of hundreds of genes Length: 968

13 p100 (contains p52 NFkB2) Name: p100 (contains p52 subunit, a.k.a. NFkB2) Descr: Once in the nucleus initiates transcription of hundreds of genes Length: 899

14 IkB Name: Inhibitor of NF kappaB beta Length: 356
Consists mostly of ankyrin repeats that serve inhibitory function

15 IkB Name: IkappaB epsilon Length: 361
Consists mostly of ankyrin repeats that serve inhibitory function

16 IKK Name: IKappaB kinase alpha Descr: Forms complexes with IKK
Length: 745 aa Conserved Serine/Threonine protein kinase Domain detected at 10 – 300 aa.

17 IKK Name: IKappaB kinase beta
Descr: Forms complexes with IKK and destroys IkB’s Length: 756 Similarly to IKK a slightly less conserved Serine/Threonine protein kinase Domain detected at aa.

18 IKK Name: IKappaB kinase gamma Length: 487 aa
Contains Chromosome segregation ATPases domain

19 az NFkB aktiválása NFkB a citoplazmában található inaktív formában mint az IkBa inhibítorához kötött p50/65 heterodimer extracelluláris indukciós hatásra az IkBa-kináz komplex (IKK) aktiválódik és foszforilálja az IkBa-t (szerin 32 és 36) amely az IkBa lizin21 és lizin22 ubiquin-kötését okozza ez az IkBa alegység lebotását eredményezi (26S proteasome) az inhibitor alegység lebomlása a p50/p65 komplex aktivációját eredményezi: az NFkB a citoplazmából a sejtmagba kerül (transzlokáció) a sejtmagban az NFkB transzkripciós faktor a ‘consensus szekvenciához’ (5’-GGGACTTTC-3’) kötődik és aktiválja a specifikus gének expresszióját

20 IkB-kináz/NEMO/IKAP komplex
Aktiváló Stimulus (kfl) gyulladási-/immun- stb. fehérjék IkB-kináz/NEMO/IKAP komplex P IkBa IkBa IkBa p50 p65 p50 p65 degradáció mRNS CITOPLAZMA p65 p50 NUKLEUSZ transzkripció p65 p50 transzlokáció Target genes

21 Reactive Oxygen Species (ROS)
Factors that induce NFkB Reactive Oxygen Species (ROS) Leukemia 16: , 2002

22 Free Radic Biol Med 25:

23 kérdés: mely szignálok aktiválják az NFkB aktivitást?

24 Table 1. A list of inducers of NF-kB activation
Cytokines TNFα , TNFβ RANKL, TRAlL CD40 ligand CD30 ligand TWEAK THANK BAFF LTβ IL-1, IL-2, IL-4 IL-8, IL-12, IL-15 IL-17, IL-18 CD11b/CD18 ligand CD2 ligand CD35 ligand CD3 ligand CD28 ligand CD43 ligand CD4 ligand CD66a ligand LlF S100B Agonist antibodies to AT1 receptor IgM ligand Beta-D-glucan ligand IgG2a Flt-1 ligand Ly6A/E ligand Growth factors and hormones GMCSF M-CSF NGF EGF Insulin-like growth factor 1 Insulin Hepatocyte growth factor Gastrin PEDF Platelet-derived growth factor Bone morphogenic protein 2 Bone morphogenic protein 4 Cortical releasing hormone Follicle-stimulating hormone Mullerian inhibiting substance PAF Plant steroids (diosgenin, hecogenin, tigogenin) Prostratin Oncogenes Ras Myc Bcr-abl All-trans retinoic acid RET/PTC3 fusion oncoprotein S100B Serum Sulphatide TGF-α TGF-β Chemical Agents L-NMA, Ethanol, Monensin Nicotine, Adriamycin 2-Deoxyglucose Anisomycin Benzyl isothiocyanate Bisperoxovanadium phosphotyrosyl Brefeldin A, Cadmium Calyculin A, Colchicine Calcium lonophore plus phorbol ester Ceramide-beta-galactose 2-chloroethyl ethyl sulfide Con A, Cycloheximide Cyclopiazonic acid Diquat, 2,4-Dinitrofluorobenzene Ferrocene, Forskolin Gadolinium chloride Glass fibers Sodium butyrate trichostatin A Malondialdehyde MDMA, MEN 17055 N-methyl-D-aspartate Mycophenolic acid Nafenopin, N-Nitrosomorphine Nocodazol, Okadaic acid Peplomycin, Phytohemagglutinin Phorbol ester, Podophy/lotoxin Polychlorinated biophenyl-77 Prostratin, Pyrogallol Staurosporine, Tunicamycin Transglutaminase 2 WF10, WY , CFTR, GPR56 Hematopoietic progenitor kinase 1 Ig heavy chain, MHC Class I

25 Table 1. A list of inducers of NF-kB activation (ctd)
Viruses Adenovirus Cytomegalovirus EBV Hammarskjöld and hepatitis B virus HVS Human herpes virus 6 HIV-1 Herpes simplex virus-1 HTLV-1 Influenza virus Measies virus Moloney murine leukemia virus Newcastle disease virus Respiratory syncytial virus Rhinovirus SARS coronavirus Sendai paramyxovirus Sindbis virus Vaccinia virus akara West Nile flavavirus Viral products Adenovírus 5: E1A Adenovirus: E3/19K African swine fever virus: IAP Antibody to dengue virus nonstructural protein 1 CMV: ie1 EBNA-2 EBV: LMP1 HBV: HBx HBV: LHBs HBV: MHBst HCV: Core protein HVS13 HVS: StpC HIV-1: gp160 HIV-1: Nef HIV-1: p9 (9 aa peptide) HIV-1:Tat HTLV-I: Tax HTLV-II: Tax Influenza vírus: hemagglutinin KSHV: K1 Parvovirus B19: NSI Respiratory syncytial virus: M2-1 SV40 Bacteria and fungi Anaplasma phagocytophilum Angiostrongylus cantonensis Bacteroides forsythus Bartonel/a henselae Bordetel/a pertussis Borrelia burgdorferi Chlamydia pneumoniae Cryptococcus neoformans Ehrlichia chaffeensis Enteropathogenic Escherichia coli Fusobacterium nucleatum Gardnerella vaginalis Helicobacter pylori Lactobacilli Listeria monocytogenes Mycoplasma fermentans Mycobacteria tuberculosis Neisseria gonorrhoeae Neisseria meningitidis Porphyromonas gingivalis Prevote/la intermedia Pseudomonas aerogenosa Rhodococcus equi Rickettsia rickettsii Salmonella dublin Salmonella typhimurium Shigella fIexneri Staphy/lococcus aureus Streptococcus Streptomyces californicus Trichomonas vaginalis Ureaplasma urealyticum Yersinia enterocolitica Bacterial/fungal products LPS Wogonin Enterotoxin GIycosylphosphatidylinositols Fumonisin B1 Staphylococcus enterotoxins A and B Apicularen A CpG Cytolysin Diphosphoryl lipid A Exotoxin 8 Lipoprotein LpK Lipoprotein LpK Lipoteichoic acid Membrane lipoproteins (Mycoplasma fermentans, Mycoplasma penetrans) Mannoproteins Muramyl peptides Mycobacterium species lipoarabinomannan PicA, PlcB Porin 1B Toxic shock syndrome toxin 1 Eukariotic parasietis Eimeria tenella and necatrix Leishmania Phospholipomannan Pneumocystis Theileria parva Trypanoplasma borreli

26 Table 1. A list of inducers of NF-kB activation (ctd)
Physiologic (stress) cond. Asthma, Rheumatoid arthritis Crohn's disease/ulcerative colitis Corneal epidemic keratoconjunctivitis Coronary artery bypass Hypercholesterolemia Hyperglycemia Hyperhomocysteinemia Hyperosmotic shock, Shear stress Hypoxia, Reoxygenation Acute jung injury Acute respiratory distress syndrome Adhesion, Hemorrhage Angina pectoris Antiphospholipid antibodies Appendicitis Depolarization Ischemia (transient, foGaI) Ischemic preconditioning Liver regeneration Biotin deficiency Butter and walnut diet Cecalligatin and puncture Mechanical ventilation Memory retrieval Middie cerebral artery occlusion Muscle disuse, Muscular dystrophy Neuronal firing Overventilation pancreatitis Proteinuria Senescence Neuroonal trimethyltin injury Uniaxial cyclic cell stretching T -cell selection Physical stress UV A, B and C radiation Bile duct ligation Cyclic mechanical muscle strain Exercice γ radiation Heavy ion irradiation High-fat diet Laminar shear stress Dietary lipid hydroperoxide PPME photosensitization Mechanical lung ventilation Obesity Wounding combined with He-Ne irradiation Wounding combened with thermal irradiathion Oxldative stress Glutathione Hydrogen peroxide Catalase Nitric oxide Ozone Peroxiynitrite Butyl peroxide Pervanadate Reoxygenation Environmental hazards Cigarette smoke Arsenic Polychlorinated biphenyl Benzo[a]pyrene diol epoxide Crocidolite asbestos fibers Dicamba Diesel exhaust particles Gliadin House dust mite Dust particles Fear-potentiated startie response Lead Lead chromate Noise Olly fly ash Silica partlcles Wood smoke Zymosan Chemotherapeutic drugs Cisplatin, Paclitaxel Doxorubicin, Tamoxifen Vinblastine, Vincristine Etoposide Ara-C Bryostatin-1 Camptothecin Daunomycin Daunorubicin Mitoxantrone Gemcitabine Therapeutic drugs Celecoxib, AZT, Ciprofibrate Bleomycin ABR SN38 SA 981, WR1065 AdAMP, Anthralin Cycloprodigiosin Dacarbasine Orengedeokuto Diazoxide 5,6-dimethylxanthenone-4-acetic acid Flavone-8-acetic acid Haloperidol Cunbi-BoshinHangam-Tang Methamphetamine Oltipraz Phenobarbital Protocatechuic acid

27 Table 1. A list of inducers of NF-kB activation (ctd)
Fatty acids Palmitate Leukotriene B4 Free fatty acids Llnolelc acid Oleic acid Saturated fattx acids Lysophosphatldlc acid Modified Proteins LDL AGEs Amyloid protein fragment Glycosylated oxyhemaglobin Maleylated bovine serum albumin Neurotrophin receptor proteolytic fragments Nonamyloid beta component of Alzheimer's disease ATM Heat shock protein HSP60 HSP71 Apoptotlc Mediators Anti-Fas/Apo-1 PARP Metals Lithium Titanium and copper implants Nickel sulfate Iron Manganase Nickel Chromium Cobalt Aluminium Natural products Areca nut extract Baicalin Beta-carotene Quercetin Quinolinic acid Safflower polysaccharides Sanglifehrin A Physiological Mediators Alloxan Angiotensin II Bradykinin Fibrinogen Hemoglobin Hyaluronan Thioredoxin Kainan acid L-Glutamate Melanin Violacein Vitamin D3 Adesonine Activin A Albumin Allergin Acrp30/adiponectin Adrenomedullin Aeginetia indica L (AIL)b-A Bronchoalveolar lavage fluid Brusatol Homocysteine Cryptdins Deoxicholic acid 12-hydroxyeicosatrienoic acid 6-Hydroxydopamine Human peptide transporter 1 LTPLyso PCNeuomelanin NS-398 Osteopontin PAF PCSC Prolactin PIF 12-Lipoxygenase Thrombin Streptozotocin Substance P Potassium Bum patient serum Anaphyloxin C3a and C5a Angiotensin II type 1 receptoractivating antibodies Antiphospholipid antibodies Basic Calcium Phosphate crystals C2-ceramide cerulein Chelidonium majus extract Collagen latice Collagen type 1 Cysteinyl leukotrines Des-Arg 10-kallidin Mixed meal ingestion Monosudium urate crystals Neutrophil elastase Phellinus linteus proteoglycan Platelet type arachidonate Polysachcharides of Poria cacos Regulatory RNA S100B Sleep deprivation TUDCA Tuberous sclerosis complex Uremic toxins, VLDL

28 Constitutive NF-kB Signaling Module
Input signal IkK IkK P P IB NF B IB P NF B NLS NF B Negative feedback IB IB Degraded IB gene NF B Cytoplasm NF B IB NF B IL-6 gene Nucleus

29 kérdés: mely szignálutak vesznek részt az NFkB aktivitásában?

30 Table 2. protein kinases implicated in NF-kB activation
Kinase Ligand IKKα Proinflammatory cytokines (eg TNF, IL-1, IL6), LPS, IkB IKKβ Proinflammatory cytokines (eg TNF, IL-1, IL6), LPS, IkB IKKγ Proinflammatory cytokines (eg TNF, IL-1, IL6), LPS, IkB IKKi/IKKε TNF, PMA, IkB NIK TNF, CD95, and IL-1 NAK Phorbol esters, growth factors PI-3K IL-1 Akt1 TNF, TCR/CD28 HPK-1 Unknown PKC-α TPA, TNF, Bimp1, Bcl1 O/MAL T1 PKC-β IgM receptor, Bimp1, BcI10/MAL T1 PKC-τ CD3-CD28 (TCR/CD28), Bimp 1, Bcl1 O/MAL T1 PKC-δ TNFα PKC-ε Phorbol ester, Bimp1, Bcl1 O/ MAL T1 aPKC TNF, ras p21 MEKK1/2 Proinflammatory cytokines MEKK3 TNF, other proinflammatory cytokines TPL-2/Cot kinase TNF pp90rsk Pseu omonas aeruglnosa Raf-1 kinase Serum ~rowth factors, phorbol ester, and PTK oncogenes PKR dsRNA TAK1/MEKK XIAP, TGF-β MLK3 CD3/CD28 PAK1 p21, LPS BTK B-cell antigen receptor JAK2 Erythropoietin PKA IL-1, LPS, many others IRAK-1 IL-1 IRAK-2 IL-1, LPs IRAK-M IL-1, LPS P56 Ick Ceramide Syk TNF, H2O2 min. 32 ismert kináz

31 mely betegségekben mutatható ki abberáns (állandóan magas)
kérdés: mely betegségekben mutatható ki abberáns (állandóan magas) NFkB aktivitás? többet tudunk, ha ismerjük a rendszer hibáit...

32 Table 3. association of NF-kB activation with diseases
Cancer B-cell lymphoma Breast cancer Hodgkin's disease Liver cancer Mantle cell lymphoma Multiple myeloma Non-Hodgkin's lymphoma Ovarian cancer Prostate cancer T -cell lymphoma Thyroid cancer Bladdercancer Colon cancer Esophagealcancer Head and neck squamous cell carcinoma Laryngealcancer Lung cancer Pancreatic cancer Pharyngealcancer Renal carcinoma Acute lymphoblastic leukemia Adult T-cell leukemia Cervical cancer Nasopharyngeal carcinoma Melanoma Cardiovascular diseases Atherosclerosis Cardiac hypertrophy Heart failure Hypercholesterolemia Diabetes mellitus Type I Type II Inflammatory diseases Alzheimer's disease Arthritis Asthma Bone resorption Chronic obstructive pulmonary disease (COPD) Crohn's disease Huntington's disease Inflammatory bowel disease Inflammatory response syndrome Multiple sclerosis Ocular allergy Parkinson's disease Other diseases Aging AIDS Catabolic disorders Ectodermal dysplasia Gut diseases Headache Helicobacter pylori-associated gastritis Inontinentia pigmenti Ischemia/reperfusion injury Systemic lupus erythematosus Muscular dystrophy Neuropathologic diseases Psychosocial stress diseases Renal diseases Sepsis Skin diseases Sleep apnea Viral infection

33 mely gének aktiválódnak az NFkB hatására?
kérdés: mely gének aktiválódnak az NFkB hatására? mi a hiba okozója (fenotípus)

34 Table 4. list of genes regulated by NF-kB
Cytokines TNF-α, TNF-β IL-1-α, IL-1β IFN-α, IFN-γ TRAlL, M-CSF RANTES FAS ligand Lymphotoxin α, β G-CSF, GM-CSF IL- 2, IL- 6, IL -8, IL- 9, IL-10, IL-11, IL-12, IL-13, IL-15 NK4, GCP-2 (CXCL6) Gro α, Gro γ, Gro-1 ICOS IL-1 receptor antagonist IP-10, KC, BMP-2 CCL 15, CCL 22, CCL 28, CCL 5 CD40 ligand CINC-1, CXCL 11 ENA-78 (CXCL5) Eotaxin Erythropoietin MCP-1/JE, MIP-1 α β MIP-2, MIP-3 α, Mob-1 Neutrophil- activating peptide 78 NK-1R Stem cell factor Angiotensinogen TCA3 TFF3 TSP-1 TSP-2 Receptors beta2 microglobulin µ-opioid receptor 2A A1 Adenosine receptor Amiloride-sensitive Na channel Androgen receptor B 7.1 Bradykinin B-1 receptor BRL-1, CCR 5, CCR 7, CD 137 CD 154, CD 23, CD 40, CD 48 CD 69, CD 83, CD 95 EGFR Gal 1 receptor, GFBP-2 Glucocorticoid receptor IGFBP-1 IL-1 receptor antagonist IL-2 receptor a-chain Ig γ4, Ig Cγ1, Ig ε heavy chain Ig к light chain, invariant chain II Lox-1, Mdr 1 MHC class (HLA-B7) MHC class I (H-2Kb) Neuropeptode YY1- receptor NMDA receptor subunint NR-1 NMDA receptor subunit Nod 2 Polymeric Ig receptor RAF receptor 1,RAGE T -cell receptor β chain T -cell receptor CD3γ TNF-Receptor, p75/80 DR4, DR5 Early response genes p62, p22/RPG1, B 94 Egr-1, TIEG Transcription factors NF-КB1, NF-КB2, c-Rel, RelB IkBα c-fos, p53, c-myb, JunB E2F3a, Elf3 , ELYS ETR 1001 IRF-1, IRF-2, IRF-4, IRF-7 Mail, Nurr1, Stat5a, WT1 Metastasis ICAM-1, VCAM-1 ELAM-1, E-selectin Endoglin, Fibronectin MadCAM-1, P-selectin Tenascin-C, DC-SIGN MMP-3, MMP-9, CXCR4 KA11/CD82, uPA Antiapoptosis Bcl-2, Bcl-XL, Bfl1/A1 TRAF-1, TRAF-2, TRAF6 c-FLIP, IAPs Survivin, A20, Bax Caspase-11 FAP-1, Fas-ligand IEX-1 L, Nr13 Angiogenesis VEGF Cell proliferation COX-2, c-myc Cell cycle Cyclin D1, P21, GADD 45 Cyclin D2, Cyclin D3 Viruses HIV-1 EBV wp promoter HBV pregenomic promoter HSV, SV-40 Adenovirus (E3 region) Avian leukosis virus Bovine leukemia virus Cytomegalovirus JC virus, HPV 16, SIV Proteins involved in antigen presentation Tapasin LMP2 TAP 1 Complement B Complement receptor 2 Complement component 3

35 Table 4. list of genes regulated by NF-kB (ctd)
Kinases PI3K PIK3 PKC8 MAP 4K1 P450 CYP2C11 CYP2E1 Oxidative stress XOD GST Mn SOD INOS Enzymes γ-GCS 11bGSD2 12-LOX 5-LOX ABC transporters ADH ARFRP1 Aromatase BACE Catepsin B and ceramide glycosyl transferase Collagenase 1 CRAD1 and 2 Dihydrodiol dehydrogenase DT –diaphorase Enzymes (ctd) Gelatinase B GSTP1-1 Guanylyl cyclase α H+-K+-ATPase a2 Heparanase HO-1 Hyaluronan synthase lodothyronine deiodinase Lysozyme MKP-1 N- Acethylglucosaminyl transferase 1 NGAL NQO1 PDE 7A1 PGES\L-PGDS Phospholipase A2 Phospholipase C δ1 PIM-1 PTGIS RACK1 REV3 Seprin 2A SNARK TERT Transglutaminase Miscellaneous α-1 acid glycoprotein a1-Antitrypsin, a2(1)-Collagen α-Fetprotein AMH Apolipoprotein C III β-Amyloid Biglycan Caveolin-1 Claudin-2 Clone 156 Clone 330 Clone 68 Connexin 32 Epsilon-globin Factor VIII Gadd45β Galectin 3 GIF GS 3686 HMG-14 K15 keratin K3 keratin K6 keratin Laminin B2 chain mCGM3 Mts1 MUC-2 Mx1 Neutrophil gelatinaseassosiated lipocalin NlF 1 P11 PAI-1 Pax 8 PCBD Perforin PGK PSA RICK S100A6 (calcyclin) Spergen-1 Syndecan-4 TFPI-2 Transferrin Urokin 16 UBE 2M UCP-2 Vimentin Wilms' tumor suppressor gene

36 kérdés: mivel gátolható az abberáns NFkB aktivitás?

37 Table 5. list of agents that inhibit NF-KB activation
Anti-inflammatory agents Aspirin, Indomethacin Diclofenac, Naproxen Dexamethasone Phenylbutazone Tamoxifen, Sulfasalazine Sulindac, Ibuprofen Leflunomide Trichodion Acetaminophen Gabexate mesilate Glucosamine sulfate Petrosaspongiolide M Dexanabinol, BSASM Cloricromene, Rolipram Pranlukast ImmuInosupressive agents Cyclosporin, LF 15-Deoxyspergualin 6(5H)-Phenanthridinone and benzamide Chemopreventive agents Carboplatin, Vesnarinone Cycloprodigiosin (- )-Cycloepoxydon Campthothecin, Gemcitabine Levamisole, Epoxomicin Angiogenesis 2-Methoxyestradiol TNP-470 Cell proliferation 6-Aminoquinazoline derivatives Raxofelast Virus K1L, HIV-1 Vpu protein Canine distemper virus Antioxidants ADT, Apocynin, Benidipine BHA, Carvedilol Catechol derivatives DHEAS, DMDTC DMSO, Disulfiram Ebselen, EPC-K1 21 Ethyl pyruvate Ethylene glycol tetraacetic acid Iron tetrakis, Mn-SOD Melatonin, NAL, NDGA Orthophenanthroline Hydroquinone and tert-butyl hydroquinone Ref-1, Tempol, Tepoxaline N-Acetylcysteine Reactive oxygen species Nitric oxide Antibacterial agents Fosfomycin 5-Aminosalicylic acid Clarithromycin Rifampicin Roxithromycin Antidiabetes agents Adiponectin Glimepiride Tyrosine phosphatase inhibitors Diamides Pervanadate Phenylarsine oxide Serine protease inhibitor Pefabloc Phosphathidyl-choline - phospholipase C inhibitor D609 HIV-1 protease inhibitors Nelfinavir Ritonavir Saquinavir ACE inhibitor Ouinadril COX-2 inhibitor Celecoxib Interferon inducible protein p202a Methanesulfonilide antiarthritis inhibitor T -614 PTK inhibitor Herbimycin A Farnesyl protein transferase inhibitor SCH66336

38 Table 5. list of agents that inhibit NF-KB activation (ctd)
Protease inhibitor Nafamostat mesilate PPARγ ligand Pioglitazone Heat shock proteins HSP70, HSP72 Statins Atorvastatin Erbstatin Fluvastatin Lovastatin Metals Chromium Cadmium Gold Lead Mercury Zink Arsenic Titanium IKB-like protein Encoded by ASFV Acetylation inhibitor HDAC Others β-Amyloid protein, β –Catenin γ-Glutamylcysteine synthetase 1,2,3,4,6-Penta-O-galloyl- beta-D-glucose 1,2,4- Thiadiazolidine derivatives 15-Deoxy-prostaglandin J(2) 17 -Allylamino-17- demethoxygeldanamycin 2-Acetylaminofluorene 3,4,5- Trimethoxy-4'- fluorochalcone 4-Hydroxy-2 -nonenal 5'-Methylthioadenosine Acrolein, Adenosine AMP-activated protein kinase Amrinone, Anandamide Angiopoietin-1, ANP Antihrombin, Antithrombin III APCO576, Arsenite Auranofin, AvrA protein AZT, Bcl-Ab1, Benfotiamine Biliverdin Biotinylated isopanepoxydone Bisphenol A, BMT Bovine serum albumin BZLF1, C5a Carbon monoxide Cyclopentones CYL-19s and CYL-26z CYLD, Desloratadine Disulfiram, Dobutamine Da 65-79, DTD E3330, E-73, Ecabet sodium Hydroquinone, Hypochlorite Inhaled isobutil nitrite Jesterone dimer, KT-90 APC Losartin, Calcitriol, CaMKK Campthothecin, Caprofin Decoy oligonucleotides Dehydroxymethylepoxy quinomicin Diethyldithiocarbamic acid Diethylmaleate Diltiazem, DMF, Epoxyquinol Erythromycin Estrogen (E2) Ethacrynic acid Ethyl 2-[(3-methyl-2,5- dioxo(3-pyrrolinyl)) Ethyl pyruvate, Evans blue Fibrates, Fish oil feeding Flunixin meglumine Flurbiprofen, Fox1j G , Gangliosides Gemfibrozil, Ghrelin GILZ, Glucocorticoids Hydroquinone, HSCO Human breast milk Hycrochloride Hyperosmolarity Hypothermia, IMD-O354 Intravenous immunoglobulin Jesterone, JSH-21, JSH-23 Kaposi's sarcoma-associated herpesvirus K1 protein Ketamine, KL-1156, LMB Macro/ide antibiotics MAST205, MEB, Melatonin Mercaptopyrazine Mesalamine, Methotrexate Monochloramine Monomethylfumarate MTA, Murr1, MX781, EM, Myxoma Virus MNF N-(p-coumaroyl) serotonin Neurofibromatosis-2 protein nicotinamide 3- aminobenzamide Nilvadipine, Nitrosoglutathione Nitrosylcobalamin mild hypothermia, N-Octylcaffeate N-Oleoyldopamine NPM-ALK oncoprotein, NRF Nucling, ox-LDL and HNE OXPAPC, pB, p53, PACAP PAN1, Panepoxidone, PBN PDTC, PEDF, Pentoxifylline Photo oxidative stress PIAS, Pirfenidone, PPM-1B Probiotics Pg J2, Pg A1, Pg E2, PSK Psychosine, PTEN , PTX-B Pyrithione, Quinazolines pyrrolidinedithiocarbamic -acid Rapamycin, Rebamipide RelA peptides, Retinoic acid receptor-related orphan receptor-alpha

39 Table 5. list of agents that inhibit NF-KB activation (ctd)
Others (ctd) Ribavirin Rifamides ,Ritonavir RKIP Rocaglamide Saline Selenomethionine Siah2, SiRNA SLPI, SOCS1 Sodium salicylate SUN C8079 Surfactant protein A Survanta TAT -SR-IКBα Tetrathiomobdate Thalidomide THI 52 Thiopental TNAP Tom1 Tranilast Triflusal Triglyceride-rich lipoproteins Troglitazone Tyrphostin Ursodeoxycholic acid Uteroglobin Vasoactive intestinal peptide vlRF3 YopJ ZAS3 protein ZUD protein

40 kérdés: hol találhatók olyan anyagok, amelyek csökentik a kóros NFkB aktivitást?

41 Table 6. natural products that suppress NF-kB activation
α-Lipoic acid α-Pinene α-Tocopherol α-Torphryl succinate β-Lapachone 1’-Acetoxychavicole acetate 20(S)-Protopanaxatriol 23-Hydroxyursolic acid 7-Amino-4-methy- coumarin Acetyl-boswellic acids Allyl-cysteine Mentoflavone Andalusol Andrographolide Anethole Apigenin Artemisia sylvatca Artemisinin Ataxanthin Astragaloside IV Aucubin Avicin Baicalein Bambara groundnut Bee venon Benzyl isothiocynate Betulinic acid Bis-eugenol Bupleurum fruticosum phenylpropanoids Cacospongionolide B Calagualine Cancer bush CAPE Capsaicin Capsiate Camosol Catalposide Cinnamaldehyde/2-methoxycinnamaldehyde Cycloepoxydon Celastrol Cepharantin Cytochalasin D Conophyline Cheongyeolsaseuplang Chromene derivatives Chicory root Chitosan Curcumin Cyclolinteinone Danshenshu DDC Dehydroascorbic acid Diarylheptanoid Dibenzylbutyrolactone lignans Diferoxamine Digitoxin Dihydroisoeugenol Dihydrolipoic acid DIM/I3C Ebselen EGCG Emodin Ent-kaurene diterpenoids Ergothioneine Evodiamine Epoxyquinone A Falcarindol Flavenoids Flavopiridol Fungal gliotoxin Ganoderma lucidum polysaccharides Garcinol Genistein Galdenamycin Genipin Ginkgolide B Glabridin Glitoxin Glossogyne tenuifolia Glycyrrhizin Guggulsterone Helenarin Hematein Herbal compound861 Hydroxyethyl starch Hypericin 10Z-hymenialdisine Hypoestoxide Indirubin-3’-oxime IRFI 042 Isomallotochromanol isomallotochromene Isorhapontigenin Kahweol Quinic acid Kamebakurin Lacidipine L-Ascorbic acid Lazaroids Lupeol Luteolin Magnolol γ-Mangostin Manassantis Mangiferin Nicotine Oleandrin Onconase Panduratin A Palthenolide PC-SPES Phenethylisothiocyanate Phomol Phytic acid Phallacidin Piceatonnol Piperine Qingkailing Shuanghuanglian Quercetin Resiniferatoxin Resveratrol Rhein Rocaglamide Rotenone Sanggenon C Sanguinarine Saucerneol Sauchinone Sesamin Sesquiterpene lactones Silymarin Sinomenine Solona nigrum L Sphondin Staurosporine Tansinones Tetrandine Theaflavin Trilinolein Triptolide Ursolic acid Vitamin C Wedalolactone Withaferin A Wogonin Wortmannin Yakuchinone A and B Zerumbone

42 Table 6. natural products that suppress NF-kB activation
Others 1,2,4-Thiadiazolidine derivatives Aged garlic extract, Apple juice Artemisia capillaris extract Blueberry and berry mix Black raspberry extracts Cat’sclaw bark, Extract of the stem bark of Mangifera indica L Extracts of Ochna macroccalyx Fomes fomentarius methanol extracts Fructus benincasae recens extract Ginkgo biloba extract Harpagophytum procumbens extracts Kochia scoparia fruit, Omega 3 fatty acids Phyllanthus amarus extracts Platycodi radix extract, Red wine Sophorae radix extract Stinging nettle plant extrats Tanacetum larvatum extract Uncaria tomentosum plant extract Trichomonas vaginalis Xanthium strumarium L Yucca schidigera extract

43 kérdés: praktikusan - mely kis-molekula- tömegű természetes vagy szintetikus anyagok csökkentik az NFkB aktivitását?

44 Table 7. proteins and peptides that inhibit NF-kB activation
Interleukin IL-4 IL-11 IL-10 IL-13 Interferon IFN-α Growth factors and hormones VEGF Hepatocyte growth factor MSH HB-EGF Chorionic gonadotropin Peptides TRAF6 inhibitory peptide NEMO binding peptide p65 binding peptide Boronic acid peptide NLS cell permeable peptides Peptide nucleic acid-DNA decoys Peptide YY TIRAP inhibitor peptide Table 8. synthetic compounds that inhibit NF-kB activation Proteosome inhibitors ALLnL PS-341 Lactacystine, β-lactone SN-50 FK506 Ro PS5190 TLCK ,TPCK Cyclosporin A DCIC Deoxyspergualin DFP LLM BTEE MG115 MG120 APNE IKK inhibitors BAY BAY BMS SPC839 AS602868 PS1145 MNL 120 SC-514 Polyubiquitination inhibitor Ro Ubiquitin Ligase Inhibitors Z-LLL, Z-LLnV P42 MAPK inhibitor AG 126 P38 MAPK inhibitor SB203580 PI-3K-kinase inhibitor LY294002 PKC inhibitor RO MEK1/2 inhibitor UO126 Protein kinase inhibitor A771726

45 kérdés: mely pontokon lehet/kell szerkezeti változtatást létrehozni (pl. rekombináns technikákkal) az NFkB aktivitásának specifikus csökkentéséhez?

46 Table 9. inhibition of NF-kB through the critical cystein residue
IKKα/β Cys179 IKKβ Cys59 IKKγ Cys417 P Cys38 p Cys62

47 kérdés: milyen célmolekulákat tervezzünk az NFkB aktivitásának csökkentsére? a szignálút melyik szakaszára?

48 kérdés: az aktivációs mechanizmus gátlásával változik-e az NFkB aktivitása? gátló stimulusok használhatók-e? hát az IkB gátlása?

49 az NF-kB gátlás kehetőségei 1.
Aktiváló Stimulus (kfl) gyulladási-/immun- stb. fehérjék IkB kináz /NEMO/IKAP P IkBa IkBa IkBa p50 p65 p50 p65 degradáció mRNS inaktív forma marad CITOPLAZMA p65 p50 NUKLEUSZ transzkripció p65 p50 transzlokáció Target genes

50 kérdés: az IkB kináz ativitásának vagy aktiválásának gátlásával lehet csökkenteni az NFkB aktivitását? mi az ubiquitináció gátlás hatása?

51 az NF-kB gátlás kehetőségei 2.
Aktiváló Stimulus (kfl) gyulladási-/immun- stb. fehérjék IkB kináz/NEMO/IKAP P IkBa IkBa IkBa p50 p65 p50 p65 degradáció mRNS inaktív forma marad CITOPLAZMA p65 p50 NUKLEUSZ transzkripció p65 p50 transzlokáció Target genes

52 az NF-kB gátlás kehetőségei 3.
Aktiváló Stimulus (kfl) gyulladási-/immun- stb. fehérjék IkB kináz/NEMO/IKAP P IkBa IkBa IkBa p50 p65 p50 p65 degradáció mRNS CITOPLAZMA p65 p50 NUKLEUSZ transzkripció p65 p50 transzlokáció Target genes

53 nem megoldott: - sejt-specificitás - alacsony toxicitás sok fejleszteni való van hátra

54 screen – ~220eFt/kísérlet
Human NFκB Signaling Pathway RT² Profiler™ PCR Array Functional Gene Grouping (more detailed information is provided in the gene table) Activation of NFκB pathwayLigands and receptors: IL1B, IL8, MYD88, TLR1, TLR2, TLR3, TLR4, TLR6, TLR8, TNF, TNFRSF10A, TNFRSF10B. Membrane molecules: IRAK1, IRAK2. Kinases: CHUK, IKBKB, IKBKG, IRAK1, IRAK2. I-kappa-B kinase/NF-kappa-B cascade: EDARADD, IKBKG, IRAK2, STAT1, TLR8. Cytoplasmic sequestering/releasing of NF-kappa-B: BCL3, IL10, NALP12, NFKBIA, TNFRSF7, TNFSF14. Transcription factors: IKBKB, IKBKG, IRAK1, NFKB1, NFKBIA, RELA, STAT1, TNF. Inflammatory response: IL1B, IL8, IRAK2, MYD88, NFKB1, TLR1, TLR2, TLR3, TLR4, TLR6, TLR8, TNF. Positive regulation of I-kappa-B kinase/NF-kappa-B cascadeLigands and receptors: CD40 (TNFRSF5), F2R, FASLG (TNFSF6), HTR2B, LTBR, SLC20A1, TICAM2, TNFRSF1A, TNFSF10, TRIF. Membrane molecules: EDG2, GJA1, HMOX1, RHOA. Kinases: IKBKE, RIPK1, TBK1. Other: BCL10, BIRC2, CARD4, CASP1, CASP8, CFLAR, CTL2, FADD, MALT1, PPM1A, REL, RFP2, TMED4 (HNLF), TRADD. NFκB Responsive GenesAcute phase response proteins: AGT, BF. Adhesion molecules: ICAM1. Extracellular molecules: BF, CSF2, CSF3, IFNA1, IFNB1, IFNG, IL6. Ligands and receptors: AGT, CCL2, ICAM1, LTA. Cytokines: CCL2, CSF2, CSF3, IFNA1, IFNB1, IFNG, IL6, IL8, LTA, TNF. Inflammatory response: CCL2. Other factors involved in NF-kappa-B pathwayExtracellular molecules: IL1A. Ligands and receptors: IL1R1, RAF1, TLR7, TLR9. Kinases: AKT1, MAP3K1, RAF1. Transcription factors: ATF1, EGR1, ELK1, FOS, JUN, NFKB2, RELB, TNFAIP3. Inflammatory response: FOS, IL1A, IL1R1, TLR7, TLR9  

55 köszönöm a figyelmet

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59 (konstitutívan) aktív NFkB-t expresszáló tumorok (pl.)
Prostate Melanoma Head and neck SCC Colon Multiple myeloma Ovarian Bladder Lung B cell lymphoma Hodgkin’s disease T-cell lymphoma Acute lymphoblastic leukemia Breast Liver Thyroid Leukemia 16: , 2002

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