cikk-referlGntrs szablyozsa: transzkripcis mechanizmusok

Dr. Marcsek Zoltn

eukaryotk promter elemeia promter elemei tbb-kevsb jl definiltak

a transzkripci start helytl klnbz tvolsgra vannakltalban vangyakran hinyzik

egy tipikus promter

az eukaryota transzkripci szablyozsa

szablyozs transzkripcis faktorokkalegy transzkripcis faktor (vagy transzkripcis faktorok egy csoportja) egy gncsoport expresszijt szablyozhatja (pl. heat shock fehrjk, G1/S restrikcis pont fehrjk, stb)egy gn trst egy vagy tbb, egymstl fggetlen transzkripcis faktor szablyozhatja (pl. metallothionine)magas expresszi kivltshoz gyakran tbb, klnbz 'response' elemhez kt transzkripcis faktor lehet szksges

Nuclear Factor-B: 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 Therapeutics2006.

NFkBmi az, mit csinl, mirt j, ha ismerjk?

transzkripcis faktor

NFkBBaltimore & Sen fedeztk fel mint egy B-sejt-specifikus magi proteint amely az immunoglobulin k knny lncnak meghatrozott szekvencijhoz ktdik s a gn trst serkenti (enhancer) (Cell 47:921-928, 1986)az NFkB a Rel transzkripcis faktor csaldba tartozik amely nagyszm, az immunvlasszal, a gyulladssal, a sejtosztdssal s apoptzissal sszefgg gn expresszijt szablyozzaaz emls sejtekben t eltr NFkB (rel) alegysget ismernk amelyek kb. 300 nagyon konzervlt aminosat tartalmaznaka citoplazmban az NFkB inaktv formban tbb, klnbz kombinciban tallhat (heterodimer p50/p65 (Rel A) s az inhibtor IkBa alegysg)

Family of NFkB and Inhibitory kB (IkB) proteinsNat.Rev.Cancer 2:301-310, 2002

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

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

IkBName: Inhibitor of NF kappaB betaLength: 356

Consists mostly of ankyrin repeats that serve inhibitory function

IkBName: IkappaB epsilonLength: 361

Consists mostly of ankyrin repeats that serve inhibitory function

IKKName: IKappaB kinase alphaDescr: Forms complexes with IKKLength: 745 aa

Conserved Serine/Threonine protein kinase Domain detected at 10 300 aa.

IKKName: IKappaB kinase betaDescr: Forms complexes with IKK and destroys IkBsLength: 756

Similarly to IKK a slightly less conserved Serine/Threonine protein kinase Domain detected at 10 - 290 aa.

IKKName: IKappaB kinase gammaLength: 487 aa

Contains Chromosome segregation ATPases domain

az NFkB aktivlsaNFkB a citoplazmban tallhat inaktv formban mint az IkBa inhibtorhoz kttt p50/65 heterodimer extracellulris indukcis hatsra az IkBa-kinz komplex (IKK) aktivldik s foszforillja az IkBa-t (szerin 32 s 36) amely az IkBa lizin21 s lizin22 ubiquin-ktst okozzaez az IkBa alegysg lebotst eredmnyezi (26S proteasome)az inhibitor alegysg lebomlsa a p50/p65 komplex aktivcijt eredmnyezi: az NFkB a citoplazmbl a sejtmagba kerl (transzlokci)a sejtmagban az NFkB transzkripcis faktor a consensus szekvencihoz (5-GGGACTTTC-3) ktdik s aktivlja a specifikus gnek expresszijt

Aktivl Stimulus(kfl)IkB-kinz/NEMO/IKAP komplexIkBap65p50IkBap65p50PIkBadegradcip65p50CITOPLAZMAp65p50NUKLEUSZmRNSgyulladsi-/immun-stb. fehrjktranszlokcitranszkripciTarget genes

Leukemia 16:1053-1068, 2002Factors that induce NFkBReactive Oxygen Species (ROS)

Free Radic Biol Med25:346-361

krds:

mely szignlok aktivljk az NFkB aktivitst?

CytokinesTNF , TNFRANKL, TRAlLCD40 ligandCD30 ligandTWEAKTHANKBAFFLTIL-1, IL-2, IL-4IL-8, IL-12, IL-15IL-17, IL-18CD11b/CD18 ligandCD2 ligandCD35 ligandCD3 ligandCD28 ligandCD43 ligandCD4 ligandCD66a ligandLlFS100BAgonist antibodies to AT1 receptorIgM ligandBeta-D-glucan ligandIgG2aFlt-1 ligandLy6A/E ligand

Growth factors and hormonesGMCSFM-CSFNGFEGFInsulin-like growth factor 1InsulinHepatocyte growth factorGastrinPEDFPlatelet-derived growth factorBone morphogenic protein 2Bone morphogenic protein 4Cortical releasing hormone Follicle-stimulating hormoneMullerian inhibiting substancePAFPlant steroids (diosgenin, hecogenin, tigogenin)ProstratinOncogenesRasMycBcr-ablAll-trans retinoic acidRET/PTC3 fusion oncoprotein S100BSerumSulphatideTGF-TGF-

Table 1. A list of inducers of NF-kB activationChemical Agents L-NMA, Ethanol, MonensinNicotine, Adriamycin2-DeoxyglucoseAnisomycinBenzyl isothiocyanateBisperoxovanadium phosphotyrosylBrefeldin A, CadmiumCalyculin A, ColchicineCalcium lonophore plus phorbol esterCeramide-beta-galactose2-chloroethyl ethyl sulfide Con A, Cycloheximide Cyclopiazonic acidDiquat, 2,4-DinitrofluorobenzeneFerrocene, ForskolinGadolinium chlorideGlass fibersSodium butyrate trichostatin AMalondialdehydeMDMA, MEN 17055N-methyl-D-aspartateMycophenolic acidNafenopin, N-NitrosomorphineNocodazol, Okadaic acidPeplomycin, PhytohemagglutininPhorbol ester, Podophy/lotoxin Polychlorinated biophenyl-77Prostratin, PyrogallolStaurosporine, TunicamycinTransglutaminase 2 WF10, WY-14 643, CFTR, GPR56Hematopoietic progenitor kinase 1Ig heavy chain, MHC Class I

Table 1. A list of inducers of NF-kB activation (ctd)VirusesAdenovirusCytomegalovirusEBVHammarskjld and hepatitis B virusHVSHuman herpes virus 6HIV-1Herpes simplex virus-1HTLV-1Influenza virusMeasies virusMoloney murine leukemia virusNewcastle disease virusRespiratory syncytial virusRhinovirusSARS coronavirusSendai paramyxovirusSindbis virusVaccinia virus akaraWest Nile flavavirusViral productsAdenovrus 5: E1AAdenovirus: E3/19KAfrican swine fever virus: IAPAntibody to dengue virus nonstructural protein 1CMV: ie1EBNA-2EBV: LMP1HBV: HBxHBV: LHBsHBV: MHBstHCV: Core proteinHVS13HVS: StpCHIV-1: gp160HIV-1: NefHIV-1: p9 (9 aa peptide)HIV-1:TatHTLV-I: TaxHTLV-II: TaxInfluenza vrus: hemagglutininKSHV: K1Parvovirus B19: NSIRespiratory syncytial virus: M2-1SV40Bacteria and fungiAnaplasma phagocytophilumAngiostrongylus cantonensis Bacteroides forsythus Bartonel/a henselae Bordetel/a pertussisBorrelia burgdorferiChlamydia pneumoniaeCryptococcus neoformans Ehrlichia chaffeensisEnteropathogenic Escherichia coliFusobacterium nucleatum Gardnerella vaginalis Helicobacter pyloriLactobacilliListeria monocytogenesMycoplasma fermentans Mycobacteria tuberculosis Neisseria gonorrhoeae Neisseria meningitidisPorphyromonas gingivalis Prevote/la intermedia Pseudomonas aerogenosa Rhodococcus equiRickettsia rickettsiiSalmonella dublinSalmonella typhimurium Shigella fIexneri Staphy/lococcus aureus StreptococcusStreptomyces californicus Trichomonas vaginalisUreaplasma urealyticum Yersinia enterocoliticaBacterial/fungal productsLPSWogoninEnterotoxinGIycosylphosphatidylinositolsFumonisin B1Staphylococcus enterotoxins A and BApicularen ACpGCytolysinDiphosphoryl lipid AExotoxin 8 Lipoprotein LpKLipoprotein LpKLipoteichoic acidMembrane lipoproteins(Mycoplasma fermentans,Mycoplasma penetrans)MannoproteinsMuramyl peptides Mycobacterium species lipoarabinomannan PicA, PlcB Porin 1BToxic shock syndrome toxin 1

Eukariotic parasietisEimeria tenella and necatrix Leishmania PhospholipomannanPneumocystisTheileria parvaTrypanoplasma borreli

Table 1. A list of inducers of NF-kB activation (ctd)Physiologic (stress) cond.Asthma, Rheumatoid arthritisCrohn's disease/ulcerative colitisCorneal epidemic keratoconjunctivitisCoronary artery bypass Hypercholesterolemia Hyperglycemia Hyperhomocysteinemia Hyperosmotic shock, Shear stressHypoxia, ReoxygenationAcute jung injuryAcute respiratory distress syndromeAdhesion, HemorrhageAngina pectoris Antiphospholipid antibodies AppendicitisDepolarizationIschemia (transient, foGaI) Ischemic preconditioning Liver regenerationBiotin deficiencyButter and walnut diet Cecalligatin and puncture Mechanical ventilation Memory retrievalMiddie cerebral artery occlusionMuscle disuse, Muscular dystrophy Neuronal firing Overventilation pancreatitis ProteinuriaSenescenceNeuroonal trimethyltin injury Uniaxial cyclic cell stretching T -cell selectionPhysical stress UV A, B and C radiation Bile duct ligationCyclic mechanical muscle strainExercice radiationHeavy ion irradiationHigh-fat dietLaminar shear stressDietary lipid hydroperoxidePPME photosensitizationMechanical lung ventilationObesityWounding combined with He-Ne irradiationWounding combened with thermal irradiathion

Oxldative stressGlutathione Hydrogen peroxide Catalase Nitric oxide OzonePeroxiynitriteButyl peroxidePervanadateReoxygenation

Environmental hazardsCigarette smokeArsenicPolychlorinated biphenyl Benzo[a]pyrene diol epoxide Crocidolite asbestos fibers DicambaDiesel exhaust particlesGliadinHouse dust miteDust particlesFear-potentiated startie responseLead Lead chromateNoiseOlly fly ashSilica partlclesWood smokeZymosanChemotherapeutic drugsCisplatin, PaclitaxelDoxorubicin, TamoxifenVinblastine, VincristineEtoposideAra-CBryostatin-1CamptothecinDaunomycinDaunorubicinMitoxantroneGemcitabine

Therapeutic drugsCelecoxib, AZT, CiprofibrateBleomycinABR-25757 SN38SA 981, WR1065AdAMP, AnthralinCycloprodigiosinDacarbasineOrengedeokutoDiazoxide5,6-dimethylxanthenone-4-acetic acidFlavone-8-acetic acidHaloperidolCunbi-BoshinHangam-TangMethamphetamineOltiprazPhenobarbitalProtocatechuic acid

Table 1. A list of inducers of NF-kB activation (ctd)Fatty acids Palmitate Leukotriene B4Free fatty acids Llnolelc acidOleic acidSaturated fattx acidsLysophosphatldlc acid

Modified Proteins LDL AGEs Amyloid protein fragment Glycosylated oxyhemaglobin Maleylated bovine serum albumin Neurotrophin receptor proteolytic fragmentsNonamyloid beta component of Alzheimer's diseaseATM

Heat shock proteinHSP60 HSP71 Apoptotlc Mediators Anti-Fas/Apo-1PARP

MetalsLithiumTitanium and copper implantsNickel sulfateIronManganaseNickelChromiumCobaltAluminium

Natural productsAreca nut extractBaicalinBeta-caroteneQuercetinQuinolinic acidSafflower polysaccharidesSanglifehrin APhysiological MediatorsAlloxanAngiotensin IIBradykininFibrinogenHemoglobinHyaluronanThioredoxinKainan acidL-GlutamateMelaninViolaceinVitamin D3AdesonineActivin AAlbuminAllerginAcrp30/adiponectinAdrenomedullinAeginetia indica L (AIL)b-ABronchoalveolar lavage fluidBrusatolHomocysteineCryptdinsDeoxicholic acid12-hydroxyeicosatrienoic acid6-HydroxydopamineHuman peptide transporter 1LTPLyso PCNeuomelaninNS-398OsteopontinPAFPCSCProlactinPIF12-LipoxygenaseThrombinStreptozotocinSubstance PPotassiumBum patient serumAnaphyloxin C3a and C5aAngiotensin II type 1 receptoractivating antibodiesAntiphospholipid antibodiesBasicCalciumPhosphate crystalsC2-ceramide ceruleinChelidonium majus extractCollagen laticeCollagen type 1Cysteinyl leukotrinesDes-Arg 10-kallidinMixed meal ingestionMonosudium urate crystalsNeutrophil elastasePhellinus linteus proteoglycanPlatelet type arachidonatePolysachcharides of Poria cacosRegulatory RNAS100BSleep deprivationTUDCATuberous sclerosis complexUremic toxins, VLDL

IkKNFBIBIB DegradedIL-6 geneNucleusCytoplasmConstitutive NF-kB Signaling ModuleIkKInput signalNLS

krds:

mely szignlutak vesznek rszt az NFkB aktivitsban?

Table 2. protein kinases implicated in NF-kB activation min. 32 ismert kinz

krds:

mely betegsgekben mutathat ki abberns (llandan magas) NFkB aktivits? tbbet tudunk, ha ismerjk a rendszer hibit...

Table 3. association of NF-kB activation with diseases CancerB-cell lymphomaBreast cancerHodgkin's diseaseLiver cancerMantle cell lymphomaMultiple myelomaNon-Hodgkin's lymphomaOvarian cancerProstate cancerT -cell lymphomaThyroid cancerBladdercancerColon cancerEsophagealcancerHead and neck squamous cell carcinomaLaryngealcancerLung cancerPancreatic cancerPharyngealcancerRenal carcinomaAcute lymphoblastic leukemiaAdult T-cell leukemiaCervical cancerNasopharyngeal carcinomaMelanomaCardiovascular diseasesAtherosclerosisCardiac hypertrophyHeart failureHypercholesterolemia

Diabetes mellitusType IType II

Inflammatory diseasesAlzheimer's diseaseArthritisAsthmaBone resorptionChronic obstructive pulmonary disease (COPD)Crohn's diseaseHuntington's diseaseInflammatory bowel diseaseInflammatory response syndromeMultiple sclerosisOcular allergyParkinson's diseaseOther diseasesAgingAIDSCatabolic disordersEctodermal dysplasiaGut diseasesHeadacheHelicobacter pylori-associated gastritisInontinentia pigmenti Ischemia/reperfusion injurySystemic lupus erythematosus Muscular dystrophyNeuropathologic diseasesPsychosocial stress diseasesRenal diseasesSepsisSkin diseasesSleep apnea Viral infection

krds:

mely gnek aktivldnak az NFkB hatsra? mi a hiba okozja (fenotpus)

Table 4. list of genes regulated by NF-kB CytokinesTNF-, TNF-IL-1-, IL-1IFN-, IFN-TRAlL, M-CSFRANTESFAS ligand Lymphotoxin , G-CSF, GM-CSFIL- 2, IL- 6, IL -8, IL- 9, IL-10, IL-11, IL-12, IL-13, IL-15NK4, GCP-2 (CXCL6) Gro , Gro , Gro-1ICOSIL-1 receptor antagonistIP-10, KC, BMP-2CCL 15, CCL 22, CCL 28, CCL 5CD40 ligandCINC-1, CXCL 11ENA-78 (CXCL5) Eotaxin Erythropoietin MCP-1/JE, MIP-1 MIP-2, MIP-3 , Mob-1Neutrophil- activating peptide 78NK-1RStem cell factorAngiotensinogenTCA3TFF3TSP-1TSP-2Receptorsbeta2 microglobulin -opioid receptor2AA1 Adenosine receptor Amiloride-sensitive Na channelAndrogen receptor B 7.1Bradykinin B-1 receptorBRL-1, CCR 5, CCR 7, CD 137CD 154, CD 23, CD 40, CD 48CD 69, CD 83, CD 95EGFRGal 1 receptor, GFBP-2Glucocorticoid receptor IGFBP-1IL-1 receptor antagonistIL-2 receptor a-chainIg 4, Ig C1, Ig heavy chain Ig light chain, invariant chain IILox-1, Mdr 1MHC class (HLA-B7) MHC class I (H-2Kb) Neuropeptode YY1- receptorNMDA receptor subunint NR-1NMDA receptor subunit Nod 2Polymeric Ig receptorRAF receptor 1,RAGET -cell receptor chainT -cell receptor CD3TNF-Receptor, p75/80 DR4, DR5Early response genesp62, p22/RPG1, B 94Egr-1, TIEG

Transcription factors NF-B1, NF-B2, c-Rel, RelBIkBc-fos, p53, c-myb, JunBE2F3a, Elf3 , ELYSETR 1001IRF-1, IRF-2, IRF-4, IRF-7Mail, Nurr1, Stat5a, WT1

Metastasis ICAM-1, VCAM-1 ELAM-1, E-selectin Endoglin, FibronectinMadCAM-1, P-selectin Tenascin-C, DC-SIGNMMP-3, MMP-9, CXCR4KA11/CD82, uPA

AntiapoptosisBcl-2, Bcl-XL, Bfl1/A1TRAF-1, TRAF-2, TRAF6c-FLIP, IAPsSurvivin, A20, BaxCaspase-11FAP-1, Fas-ligandIEX-1 L, Nr13AngiogenesisVEGF

Cell proliferationCOX-2, c-myc

Cell cycleCyclin D1, P21, GADD 45Cyclin D2, Cyclin D3

VirusesHIV-1EBV wp promoterHBV pregenomic promoterHSV, SV-40Adenovirus (E3 region)Avian leukosis virusBovine leukemia virus CytomegalovirusJC virus, HPV 16, SIV

Proteins involved in antigen presentation TapasinLMP2TAP 1Complement BComplement receptor 2Complement component 3

Table 4. list of genes regulated by NF-kB (ctd)KinasesPI3KPIK3PKC8MAP 4K1

P450CYP2C11CYP2E1

Oxidative stress XODGSTMn SOD INOS

Enzymes-GCS11bGSD212-LOX5-LOXABC transporters ADHARFRP1AromataseBACECatepsin B and ceramide glycosyl transferase Collagenase 1CRAD1 and 2 Dihydrodiol dehydrogenaseDT diaphoraseEnzymes (ctd)Gelatinase B GSTP1-1Guanylyl cyclase H+-K+-ATPase a2 HeparanaseHO-1Hyaluronan synthase lodothyronine deiodinaseLysozymeMKP-1N- Acethylglucosaminyl transferase 1NGALNQO1PDE 7A1PGES\L-PGDS Phospholipase A2Phospholipase C 1PIM-1PTGISRACK1REV3Seprin 2ASNARKTERTTransglutaminase

Miscellaneous-1 acid glycoprotein a1-Antitrypsin,a2(1)-Collagen-FetproteinAMHApolipoprotein C III-AmyloidBiglycanCaveolin-1Claudin-2Clone 156Clone 330Clone 68Connexin 32Epsilon-globinFactor VIIIGadd45Galectin 3GIFGS 3686HMG-14K15 keratinK3 keratin K3 keratin K6 keratinLaminin B2 chainmCGM3Mts1MUC-2Mx1Neutrophil gelatinaseassosiated lipocalinNlF 1P11PAI-1Pax 8PCBDPerforinPGKPSARICKS100A6 (calcyclin) Spergen-1 Syndecan-4TFPI-2TransferrinUrokin 16UBE 2MUCP-2VimentinWilms' tumor suppressor gene

krds:

mivel gtolhat az abberns NFkB aktivits?

Table 5. list of agents that inhibit NF-KB activationAnti-inflammatoryagentsAspirin, IndomethacinDiclofenac, NaproxenDexamethasonePhenylbutazoneTamoxifen, SulfasalazineSulindac, IbuprofenLeflunomide Trichodion Acetaminophen Gabexate mesilate Glucosamine sulfate Petrosaspongiolide M Dexanabinol, BSASMCloricromene, RolipramPranlukast

ImmuInosupressive agentsCyclosporin, LF15-019515-Deoxyspergualin6(5H)-Phenanthridinone and benzamide

Chemopreventive agentsCarboplatin, VesnarinoneCycloprodigiosin(- )-Cycloepoxydon Campthothecin, GemcitabineLevamisole, EpoxomicinAngiogenesis2-Methoxyestradiol TNP-470

Cell proliferation 6-Aminoquinazoline derivatives Raxofelast

VirusK1L, HIV-1 Vpu protein Canine distemper virus

AntioxidantsADT, Apocynin, BenidipineBHA, CarvedilolCatechol derivativesDHEAS, DMDTCDMSO, DisulfiramEbselen, EPC-K1 21Ethyl pyruvateEthylene glycol tetraacetic acidIron tetrakis, Mn-SODMelatonin, NAL, NDGAOrthophenanthrolineHydroquinone and tert-butyl hydroquinoneRef-1, Tempol, TepoxalineN-Acetylcysteine

Reactive oxygen speciesNitric oxideAntibacterial agentsFosfomycin 5-Aminosalicylic acid ClarithromycinRifampicinRoxithromycin

Antidiabetes agentsAdiponectinGlimepiride

Tyrosine phosphatase inhibitorsDiamidesPervanadatePhenylarsine oxide

Serine protease inhibitorPefabloc

Phosphathidyl-choline - phospholipase C inhibitorD609

HIV-1 protease inhibitors NelfinavirRitonavirSaquinavir

ACE inhibitor Ouinadril

COX-2 inhibitorCelecoxib

Interferon inducible proteinp202a

Methanesulfonilide antiarthritis inhibitor T -614

PTK inhibitorHerbimycin A

Farnesyl protein transferase inhibitor SCH66336

Table 5. list of agents that inhibit NF-KB activation (ctd)Protease inhibitor Nafamostat mesilate

PPAR ligandPioglitazone

Heat shock proteinsHSP70, HSP72

StatinsAtorvastatinErbstatinFluvastatinLovastatin

MetalsChromium Cadmium GoldLeadMercuryZinkArsenicTitanium IKB-like proteinEncoded by ASFV

Acetylation inhibitorHDACOthers-Amyloid protein, Catenin-Glutamylcysteinesynthetase1,2,3,4,6-Penta-O-galloyl- beta-D-glucose1,2,4- Thiadiazolidine derivatives 15-Deoxy-prostaglandin J(2)17 -Allylamino-17- demethoxygeldanamycin 2-Acetylaminofluorene3,4,5- Trimethoxy-4'- fluorochalcone4-Hydroxy-2 -nonenal5'-MethylthioadenosineAcrolein, AdenosineAMP-activated protein kinaseAmrinone, AnandamideAngiopoietin-1, ANPAntihrombin, Antithrombin IIIAPCO576, ArseniteAuranofin, AvrA proteinAZT, Bcl-Ab1, BenfotiamineBiliverdinBiotinylated isopanepoxydoneBisphenol A, BMTBovine serum albuminBZLF1, C5aCarbon monoxideCyclopentonesCYL-19s and CYL-26zCYLD, DesloratadineDisulfiram, DobutamineDa 65-79, DTD

E3330, E-73, Ecabet sodiumHydroquinone, HypochloriteInhaled isobutil nitriteJesterone dimer, KT-90 APCLosartin, Calcitriol, CaMKKCampthothecin, CaprofinDecoy oligonucleotidesDehydroxymethylepoxy quinomicinDiethyldithiocarbamic acid DiethylmaleateDiltiazem, DMF, EpoxyquinolErythromycinEstrogen (E2)Ethacrynic acidEthyl 2-[(3-methyl-2,5- dioxo(3-pyrrolinyl))Ethyl pyruvate, Evans blueFibrates, Fish oil feedingFlunixin meglumineFlurbiprofen, Fox1jG-120 3032, GangliosidesGemfibrozil, GhrelinGILZ, GlucocorticoidsHydroquinone, HSCOHuman breast milk HycrochlorideHyperosmolarity Hypothermia, IMD-O354Intravenous immunoglobulin Jesterone, JSH-21, JSH-23Kaposi's sarcoma-associated herpesvirus K1 proteinKetamine, KL-1156, LMBMacro/ide antibioticsMAST205, MEB, MelatoninMercaptopyrazineMesalamine, MethotrexateMonochloramineMonomethylfumarateMTA, Murr1, MX781, EM, Myxoma Virus MNF N-(p-coumaroyl) serotonin Neurofibromatosis-2 protein nicotinamide 3- aminobenzamideNilvadipine, Nitrosoglutathione Nitrosylcobalamin mild hypothermia, N-OctylcaffeateN-OleoyldopamineNPM-ALK oncoprotein, NRFNucling, ox-LDL and HNEOXPAPC, pB, p53, PACAPPAN1, Panepoxidone, PBNPDTC, PEDF, PentoxifyllinePhoto oxidative stress PIAS, Pirfenidone, PPM-1BProbioticsPg J2, Pg A1, Pg E2, PSKPsychosine, PTEN , PTX-BPyrithione, Quinazolinespyrrolidinedithiocarbamic -acid Rapamycin, RebamipideRelA peptides, Retinoic acid receptor-related orphan receptor-alpha

Table 5. list of agents that inhibit NF-KB activation (ctd)Others (ctd)RibavirinRifamides ,RitonavirRKIPRocaglamideSalineSelenomethionineSiah2, SiRNASLPI, SOCS1Sodium salicylateSUN C8079Surfactant protein ASurvantaTAT -SR-IBTetrathiomobdateThalidomide THI 52ThiopentalTNAPTom1TranilastTriflusalTriglyceride-rich lipoproteinsTroglitazone Tyrphostin Ursodeoxycholic acid Uteroglobin Vasoactive intestinal peptidevlRF3YopJZAS3 proteinZUD protein

krds:

hol tallhatk olyan anyagok, amelyek cskentik a kros NFkB aktivitst?

Table 6. natural products that suppress NF-kB activation -Lipoic acid -Pinene-Tocopherol -Torphryl succinate -Lapachone1-Acetoxychavicole acetate20(S)-Protopanaxatriol23-Hydroxyursolic acid7-Amino-4-methy- coumarinAcetyl-boswellic acidsAllyl-cysteineMentoflavoneAndalusolAndrographolideAnetholeApigeninArtemisia sylvatcaArtemisininAtaxanthinAstragaloside IVAucubinAvicinBaicaleinBambara groundnutBee venonBenzyl isothiocynateBetulinic acidBis-eugenolBupleurum fruticosum phenylpropanoidsCacospongionolide BCalagualineCancer bushCAPECapsaicinCapsiateCamosolCatalposideCinnamaldehyde/2-methoxycinnamaldehydeCycloepoxydonCelastrolCepharantinCytochalasin DConophylineCheongyeolsaseuplangChromene derivativesChicory rootChitosanCurcuminCyclolinteinoneDanshenshuDDCDehydroascorbic acidDiarylheptanoidDibenzylbutyrolactone lignansDiferoxamineDigitoxinDihydroisoeugenolDihydrolipoic acidDIM/I3CEbselenEGCGEmodinEnt-kaurene diterpenoidsErgothioneineEvodiamine

Epoxyquinone AFalcarindolFlavenoidsFlavopiridolFungal gliotoxinGanoderma lucidum polysaccharidesGarcinolGenisteinGaldenamycinGenipinGinkgolide BGlabridinGlitoxinGlossogyne tenuifoliaGlycyrrhizinGuggulsteroneHelenarinHemateinHerbal compound861Hydroxyethyl starchHypericin10Z-hymenialdisineHypoestoxideIndirubin-3-oximeIRFI 042Isomallotochromanol isomallotochromeneIsorhapontigeninKahweol Quinic acidKamebakurinLacidipineL-Ascorbic acidLazaroidsLupeolLuteolinMagnolol-MangostinManassantisMangiferinNicotineOleandrinOnconasePanduratin APalthenolidePC-SPESPhenethylisothiocyanatePhomolPhytic acidPhallacidinPiceatonnolPiperineQingkailingShuanghuanglianQuercetinQuercetinResiniferatoxinResveratrolRheinRocaglamideRotenoneSanggenon CSanguinarineSaucerneolSauchinoneSesaminSesquiterpene lactonesSilymarinSinomenineSolona nigrum LSphondinStaurosporineTansinonesTetrandineTheaflavinTrilinoleinTriptolideUrsolic acidVitamin CWedalolactoneWithaferin AWogoninWortmanninYakuchinone A and BZerumbone

Table 6. natural products that suppress NF-kB activationOthers1,2,4-Thiadiazolidine derivativesAged garlic extract, Apple juiceArtemisia capillaris extractBlueberry and berry mixBlack raspberry extractsCatsclaw bark, Extract of the stem bark of Mangifera indica LExtracts of Ochna macroccalyxFomes fomentarius methanol extractsFructus benincasae recens extractGinkgo biloba extractHarpagophytum procumbens extractsKochia scoparia fruit, Omega 3 fatty acidsPhyllanthus amarus extractsPlatycodi radix extract, Red wineSophorae radix extractStinging nettle plant extrats Tanacetum larvatum extractUncaria tomentosum plant extractTrichomonas vaginalisXanthium strumarium LYucca schidigera extract

krds:

praktikusan - mely kis-molekula- tmeg termszetes vagy szintetikus anyagok cskkentik az NFkB aktivitst?

Table 7. proteins and peptides that inhibit NF-kB activation Interleukin IL-4IL-11IL-10IL-13

InterferonIFN-

Growth factors and hormonesVEGFHepatocyte growth factor MSH HB-EGFChorionic gonadotropin

PeptidesTRAF6 inhibitory peptideNEMO binding peptidep65 binding peptideBoronic acid peptideNLS cell permeable peptides Peptide nucleic acid-DNA decoys Peptide YYTIRAP inhibitor peptideTable 8. synthetic compounds that inhibit NF-kB activation IKK inhibitors BAY-11-7082 BAY-11-7085 BMS-345541 SPC839 AS602868 PS1145MNL 120SC-514

Polyubiquitination inhibitor Ro106-9920

Ubiquitin Ligase Inhibitors Z-LLL, Z-LLnV

Proteosome inhibitorsALLnL PS-341Lactacystine, -lactone SN-50FK506Ro106-9920PS5190TLCK ,TPCKCyclosporin ADCICDeoxyspergualinDFPLLMBTEEMG115 MG120APNE P42 MAPK inhibitor AG 126

P38 MAPK inhibitor SB203580

PI-3K-kinase inhibitor LY294002

PKC inhibitor RO31-8220

MEK1/2 inhibitor UO126

Protein kinase inhibitor A771726

krds:

mely pontokon lehet/kellszerkezeti vltoztatst ltrehozni (pl. rekombinns technikkkal) az NFkB aktivitsnak specifikus cskkentshez?

Table 9. inhibition of NF-kB through the critical cystein residue IKK/ Cys179IKK Cys59IKK Cys417P65 Cys38p50 Cys62

krds:

milyen clmolekulkat tervezznk az NFkB aktivitsnak cskkentsre? a szignlt melyik szakaszra?

krds:

az aktivcis mechanizmus gtlsval vltozik-e az NFkB aktivitsa? gtl stimulusok hasznlhatk-e? ht az IkB gtlsa?

Aktivl Stimulus(kfl)IkB kinz /NEMO/IKAPIkBap65p50IkBap65p50PIkBadegradcip65p50CITOPLAZMAp65p50NUKLEUSZmRNStranszlokcitranszkripciTarget genesaz NF-kB gtls kehetsgei 1.inaktv forma maradgyulladsi-/immun-stb. fehrjk

krds:

az IkB kinz ativitsnak vagyaktivlsnak gtlsval lehet cskkenteni az NFkB aktivitst? mi az ubiquitinci gtls hatsa?

Aktivl Stimulus(kfl)IkB kinz/NEMO/IKAPIkBap65p50IkBap65p50PIkBadegradcip65p50CITOPLAZMAp65p50NUKLEUSZmRNStranszlokcitranszkripciTarget genesaz NF-kB gtls kehetsgei 2.inaktv forma maradgyulladsi-/immun-stb. fehrjk

Aktivl Stimulus(kfl)IkB kinz/NEMO/IKAPIkBap65p50IkBap65p50PIkBadegradcip65p50CITOPLAZMAp65p50NUKLEUSZmRNStranszlokcitranszkripciTarget genesaz NF-kB gtls kehetsgei 3.gyulladsi-/immun-stb. fehrjk

nem megoldott:- sejt-specificits- alacsony toxicits

sok fejleszteni val van htra

screen ~220eFt/ksrletHuman NFB Signaling Pathway RT Profiler PCR Array Functional Gene Grouping (more detailed information is provided in the gene table) Activation of NFB 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. NFB 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

ksznm a figyelmet

Leukemia 16:1053-1068, 2002(konstitutvan) aktv NFkB-t expresszl tumorok (pl.)B cell lymphomaHodgkins diseaseT-cell lymphomaAcute lymphoblastic leukemiaBreastLiverThyroidProstateMelanomaHead and neck SCCColonMultiple myelomaOvarianBladder Lung