A Beginner's Guide to NF-B Signaling Pathways

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    Ann. N.Y. Acad. Sci. 1030: 113 (2004). 2004 New York Academy of Sciences.doi: 10.1196/annals.1329.002

    A Beginners Guide to NF-

    k

    B Signaling Pathways

    SYLVIE DELHALLE, ROMAIN BLASIUS, MARIO DICATO,AND MARC DIEDERICH

    a

    Laboratoire de Biologie Molculaire et Cellulaire du Cancer, Hpital Kirchberg, Luxembourg

    A

    BSTRACT

    : Nuclear factor

    k

    B (NF-

    k

    B) belongs to a family of heterodimerictranscription factors that play a key role in inflammatory and stress re-sponses as well as in tumor cell resistance to apoptosis. These effects are dueto the NF-

    k

    B-dependent transcription of many proinflammatory and antiapo-ptotic genes, whose products ensure various cell responses to environmentalconditions. The signal transduction pathways leading to NF-

    k

    B activation arewell characterized, and the different steps implicated in these pathways involveproteins that could constitute targets for NF-

    k

    B inhibition. Several inhibitorsaiming to prevent NF-

    k

    B activity and thus the transcription of target genes arestudied, and a few compounds seem particularly promising. We try here tosummarize the advantages that can issue from various studies on NF-

    k

    B.

    K

    EYWORDS

    : NF-

    k

    B; apoptosis; inflammation; cancer

    INTRODUCTION

    The nuclear factor

    k

    B (NF-

    k

    B) transcription factor is a dimeric complex of vari-ous subunits that belong to the Rel family (p105/50, p100/52, p65 [RelA], RelB, andc-Rel). NF-

    k

    B proteins all share a 300-amino acid domain, the Rel homology do-main (RHD), allowing DNA binding, dimerization, and nuclear localization. NF-

    k

    Bproteins reside normally in the cytoplasm, where they are sequestered by a family ofinhibitors of

    k

    B (I

    k

    B) proteins through interactions between inhibitors ankyrin re-peats and the RHD. Upon stimulation of the cells by various activators such ascytokines, lipopolysaccharide, growth factors, stress inducers, chemotherapeuticagents, and other stimuli, I

    k

    B is phosphorylated on two serine residues, which trig-gers its ubiquitinylation and degradation by the 26S proteasome. NF-

    k

    B is then freeto enter the nucleus and to activate the transcription of target genes by binding to itscognate decameric DNA sequence 5

    -GGGRNNYYCC-3

    , where R indicates A orG, Y indicates C or T, and N can be any base. NF-

    k

    B is involved in the transcriptionof many proinflammatory as well as antiapoptotic genes and is thus a key player inthe progression of carcinogenesis and inflammatory diseases such as rheumatoidarthritis, inflammatory bowel disease, and asthma.

    1

    Therapies aiming to suppress

    a

    Address for correspondence: Marc Diederich, Laboratoire de Biologie Molculaire et Cellu-laire du Cancer, Hpital Kirchberg, L-2540 Luxembourg, Luxembourg. Voice:

    +

    352-2468-4040;fax:

    +

    352-2468-4060.e-mail: marc.diederich@education.lu

  • 2 ANNALS NEW YORK ACADEMY OF SCIENCES

    NF-

    k

    B-induced survival genes are thus an interesting approach to fight and curethese diseases. The purpose of this brief review is to summarize the role of NF-

    k

    Bin cell proliferation and the different ways of inhibiting its activity.

    NF-

    k

    B ACTIVATION PATHWAY

    Activation of NF-

    k

    B through I

    k

    B phosphorylation and degradation depends onthe activation of I

    k

    B kinases (IKKs). The IKK complex is composed of three sub-units, the catalytic subunits IKK

    a

    and IKK

    b

    and the regulatory subunit IKK

    g

    (or NEMO,NF-

    k

    B essential modulator), and was originally identified as a high-molecular-weightkinase complex able to phosphorylate serines 32 and 36 of I

    k

    B

    a

    .

    2

    The differentcomponents of this complex have been further identified and characterized,

    37

    andknock-out experiments have determined their role in NF-

    k

    B activation. From thesestudies, it appears that IKK

    g

    is absolutely required for IKK activity and classical NF-

    k

    B activation through the I

    k

    B phosphorylation and degradation pathways

    8,9

    but notfor the alternative pathway leading to p52/RelB dimer translocation.

    10

    IKK

    b

    genedisruption in mice leads to death between days 12.5 and 14.5 after gestation frommassive liver apoptosis, whereas IKK

    a

    gene suppression results in defective kerati-nocyte differentiation.

    IKK

    b

    and IKK

    g

    are required for the canonical pathway of I

    k

    B phosphorylationand degradation in response to proinflammatory stimuli, whereas IKK

    a

    is dispens-able for I

    k

    B phosphorylation but is involved and necessary for inducible p100 pro-cessing. RelBp100 forms an inactive dimer, and the IKK

    a

    -dependent degradationof the C-terminal part of p100 allows nuclear translocation of the formed RelBp52complex. Activation of this dimer is important for lymphoid organ development andadaptive immune response but not for other NF-

    k

    B-dependent functions such asapoptosis inhibition and innate immunity.

    11,12

    NF-

    k

    B AND APOPTOSIS

    Apoptosis is a kind of cell death characterized by morphological changes and in-volves the activation of a family of cysteine aspartate proteases called caspases.These proteases preexist in unstimulated cells as inactive zymogens and must be ac-tivated by proteolytic cleavage to form a heterotetramer consisting of two large andtwo small subunits. Two major ways of caspase activation are well characterized todate: the death receptors (DR) or extrinsic pathway, and the mitochondrial or intrin-sic pathway.

    13

    Apoptotic signaling through the extrinsic pathway is triggered by the engagementof members of the tumor necrosis factor (TNF) receptor family (TNFR1, Fas/CD95,DR3, DR4, DR5, and DR6) by their ligands (TNF

    a

    , lymphotoxin

    a

    , FasL, Apo3L,and TNF-related apoptosis-inducing ligand), resulting in receptor trimerization andactivation of procaspase-8 and -10. DNA damage or cell stress leading to the activa-tion of p53 or the Bcl-2 family proapoptotic proteins such as Bax and Bak initiate the in-trinsic pathway and induce the mitochondrial release of apoptogenic molecules suchas cytochrome

    c

    , apoptosis-inducing factor, or Smac/DIABLO (second mitochondria-derived activator of caspases/direct inhibitors of apoptosis [IAP]-binding protein

  • 3DELHALLE

    et al.

    : BEGINNERS GUIDE TO NF-

    k

    B SIGNALING PATHWAYS

    with low pI). Cytochrome

    c

    binds to the apoptotic protease-activating factor-1, and thisdimer forms the apoptosome complex with procaspase-9.

    14

    Interconnection existsbetween the extrinsic and intrinsic pathways, since caspase-8 proteolysis through theextrinsic pathway leads to cleavage and activation of Bid, a proapoptotic member ofthe Bcl-2 family. Once cleaved, truncated Bid incorporates into the mitochondrialmembrane and induces cytochrome c release, which in turns leads to apoptosomeformation and thus the intrinsic apoptotic pathway.

    15

    Antiapoptotic Role

    Transcription factors of the NF-

    k

    B family play a role in the regulation of the apo-ptotic program in different cell lines.

    16

    The first evidence of the NF-

    k

    B cytoprotec-tive role came from the analysis of p65

    -

    /

    -

    mice dying on embryonic day 15 frommassive liver apoptosis, which could be corrected by p65 reexpression.

    17,18

    NF-

    k

    Btranscriptional activity leads to the expression of many antiapoptotic genes. Amongthose gene products, some are directly implicated in repressing and blocking theapoptotic cascade, such as IAPs, c-FLIP (caspase-8/FADD-like-IL-1

    b

    -convertingenzyme inhibitory protein), or Bcl-2 family proteins.

    IAPs are a family of antiapoptotic proteins highly conserved throughout evolu-tion that have the ability to inhibit the activation of various caspases by direct bind-ing and interaction through their baculoviral inhibitory repeat.

    19

    NF-

    k

    B inhibitsTNF-

    a

    -induced apoptosis through transcriptional activation of IAP1, IAP2, and TNFreceptor-associated factor (TRAF) 1 and TRAF2, thus inhibiting caspase-8 activity.

    20

    c-FLIP is a proteolytically inactive analog of caspase-8 and competes with pro-caspase-8 and -10 for binding to FADD, thus preventing their activation and subse-quent apoptosis.

    21,22

    Bcl-2 family proteins such as Bfl-1/A1, Bcl-XL and Bcl-2 prevent apoptosis byinhibiting cytochrome

    c

    leakage from the mitochondria, thus avoiding apoptosomeformation and the apoptotic cascade.

    NF-

    k

    B activation also leads to repression of several proapoptotic genes. For exam-ple, two genes coding for the transcription factors Forkhead and Growth Arrest and DNADamage-inducible gene 153/C/EBP-homologous protein

    23,24

    as well as the proapoptoticgene

    bax25,26 are repressed by the activity of NF-k B. NF-k B activation also interfereswith p53 proapoptotic function, since both transcription factors can inhibit each otherstranscriptional activity by competing for a limiting pool of CBP/p300 complexes.26

    Proapoptotic Role

    NF- k B may have proapoptotic activity in some cell types under certain condi-tions. It regulates the expression of genes whose products can induce apoptosis, suchas the TNF receptor superfamily members DR4, DR5, DR6, Fas, and the FasLligand.2730 Moreover, NF- k B activity can sometimes be correlated to apoptosis.NF- k B is activated during serum starvation-induced human embryonic kidney cellapoptosis, and its inhibition partially protects cells from this death.31 Glutamate-induced neuronal toxicity is avoided by treatment with the NF-k B inhibitor sodiumsalicylate,32,33 and NF- k B is also involved in the apoptosis occurring during aviandevelopment.34 More recently, NF- k B activity has been shown essential todaunomycin-induced apoptosis.35

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    NF-kB AND DRUG RESISTANCE

    NF- k B activity confers an increased resistance of cancer cells to chemotherapeu-tic drugs. For instance, overexpression of a mutant Ik B a protein sensitizes colorectalcancer lineage LOVO to irinotecan (camptothecin-11), a topoisomerase I poison,and induces apoptosis in HT1080 fibrosarcoma cells treated with irinotecan, dauno-rubicin, or ionizing radiation.36,37 NF- k B also regulates genes that modulate cellulardrug uptake or elimination, such as multidrug resistance-1, encoding the P-glycopro-tein membrane transporter38,39 and glutathione S-transferase p1-1.40

    NF-kB AND CARCINOGENESIS

    Several studies suggest that NF-k B family members are involved in cancer devel-opment.4143 The first evidence establishing a role for NF-k B in carcinogenesiscame from the fact that c-Rel is the human counterpart of v-Rel, a viral oncogenecausing leukemia and lymphoma in chickens, mice, and transgenic animals.44,45Moreover, many cancers are associated with gene amplification or chromosomictranslocation of genes such as p65, c-rel, nf- k b1, nf- k b2, bcl-3, i k b a , and i k b.4650Constitutive activity of NF- k B is also observed in various tumors and hematologicalmalignancies. For example, high levels of constitutively active NF- k B are found inHodgkins lymphoma ReedSternberg cells, and functional inhibition of this tran-scription factor facilitates apoptosis.5153 This constitutive activation in ReedStern-berg cells is linked to mutations of the genes coding for Ik Ba and Ik B inhibitors,5456although ligand-independent activation of CD30 receptors leading to TRAF aggre-gation and NF- k B stimulation has recently been described.57,58 Elevated NF- k Bactivities were detected in a variety of tumors, including hormone-dependent and-independent breast cancers as well as chemically induced breast cancers in ro-dents.48,5962 Several viral oncoproteins, such as Tax from the human T-cell leuke-mia virus type 1, hepatitis virus protein HBx, and latent membrane protein 1 fromEpstein-Barr virus, activate NF- k B during the cell transformation process.6366

    NF-kB AND INFLAMMATION

    Numerous proinflammatory mediators, such as interleukin (IL)-1 and TNF a , in-duce nuclear translocation of NF-k B, which in turn activates the transcription ofgene products involved in the inflammatory response, angiogenesis, and cell adhe-sion. NF- k B promotes the expression of cell adhesion molecules (intercellular ad-hesion molecule [ICAM]-1, vascular cell adhesion molecule [VCAM]-1, E selectin,tenascin C), vascular endothelial growth factor, and matrix metalloprotease-2 and-9, which are responsible for degradation of the extracellular matrix.67 This transcrip-tion factor is also involved in the transcription of genes coding for enzymes such asinducible nitric oxide synthase, cyclooxygenase (COX)-2, 5- and 12-lipooxygenase,chemokines, and cytokines (IL-1 and TNF a ). COX-2 is upregulated in aggressivecolorectal cancers and has been found to promote angiogenesis. Mediators such asnitric oxide, prostaglandins, IL-1, and TNF a are involved in the regulation of bloodpressure, platelet aggregation, and body temperature. Moreover, NF-k B is also impor-tant in the transcription of genes coding for several acute-phase proteins.

  • 5DELHALLE et al.: BEGINNERS GUIDE TO NF-kB SIGNALING PATHWAYS

    NF-k B constitutive activity seems to play a role in chronic inflammatory diseasessuch as inflammatory bowel disease, Crohns disease, ulcerative colitis, rheumatoid ar-thritis, and asthma.1 NF-k B activation in chronic inflammation may participate in tumorinitiation, since the antiapoptotic genes activated by this transcription factor may contrib-ute to the survival of altered cells that would otherwise be committed to apoptosis andthereby allow the formation of precancerous lesions. For instance, Helicobacter pyloriinfections or constitutive activation of the IL-1 gene, both triggering NF-k B activation,are risk factors for the development of gastric cancer.68,69 Constitutive NF-k B activationmay also be responsible for the development of colitis-associated cancer in patients suf-fering from inflammatory bowel disease, ulcerative colitis, or Crohns disease.7072

    NF-kB INHIBITION

    The identification of NF-k B as a key player in apoptosis resistance and inflam-matory diseases underscores the potential benefits of its inhibition. Several steps ofthe NF- k B signal transduction pathway, such as IKK activation, I k B phosphoryla-tion and degradation, NF- k B nuclear translocation, and transcriptional activity, canbe targeted by various inhibitors (FIG. 1).

    IKK Inhibitors

    The IKK kinases constitute the apical complex responsible for NF-k B activation,and the effects of many inhibitory compounds on this complex have thus been studied.

    Nonsteroidal Anti-Inflammatory DrugsAnti-inflammatory agents such as acetylsalicylic acid and sodium salicylate exert

    their effect at least partially through NF-k B inhibition, mediated by competitive in-hibition of the ATP-binding site of IKKb .73,74 Sulfasalazine has also been shown toinhibit NF- k B through binding to IKKb and repressing its catalytic activity.75 Sulin-dac and its metabolites, sulindac sulfide and sulindac sulfone, also interfere with theNF- k B activation pathway by inhibiting IKK activity.76

    Cyclopentenone ProstaglandinsCyclopentenone prostaglandins such as prostaglandin A1 and 15-deoxy- D 12-14-

    PGJ2 are irreversible inhibitors of IKKb by covalent modifications of cysteine resi-dues.77 Moreover, covalent changes in NF- k B subunits leading to binding impair-ment have also been observed with the same compounds.78,79

    Natural CompoundsFlavonoids are naturally occurring phenolic compounds present in plants that ex-

    hibit anti-inflammatory and cancer-preventing properties. Different studies haveshown that flavonoids exert some of these effects by inhibiting NF-k B and subse-quent transcription of proinflammatory or antiapoptotic genes. For example, curcumin(a yellow extract from turmeric), capsaicin (extract from red pepper), resveratrol (redwine polyphenol), and green tea polyphenols are potent inhibitors of NF-k B activityby preventing IKK activity.8087

  • 6 ANNALS NEW YORK ACADEMY OF SCIENCES

    Glucocorticoids

    Glucocorticoids (GCs) are widely used anti-inflammatory compounds known toinhibit proinflammatory gene products such as COX-2 and TNF. GCs exert their ef-fects by inducing the binding of the glucocorticoid receptor (GR) family of ligand-dependent transcription factors to their DNA glucocorticoid response elements. GRsinduce the synthesis of I k B a , and this newly synthesized inhibitor is able to complexNF- k B and thus prevent its activity.88,89 However, this mechanism is not the only

    FIGURE 1. Different approaches to inhibit NF- k B activation according to the molecu-lar target of the pathway. Several steps involving different molecular intermediates are pos-sible targets for NF- k B inhibitors. Peptides such as NEMO binding domain (NBD) peptideprevent IKK complex formation, whereas cyclopentenone prostaglandins (CyPGs), nonste-roidal anti-inflammatory drugs (NSAIDs), and natural compounds inhibit IKK activation.Proteasome inhibitors block I k B degradation, and glucocorticoids induce its neosynthesis.Finally, nuclear localization sequence (NLS)-based peptides inhibit NF- k B nuclear translo-cation, whereas antisense or decoy oligonucleotides prevent the transcription of target genes.

  • 7DELHALLE et al.: BEGINNERS GUIDE TO NF-kB SIGNALING PATHWAYS

    one by which GRs repress NF-k B-dependent transactivation. GCs are also involvedin the inhibition of RNA polymerase II phosphorylation,90 the inhibition of p65-mediated histone acetyltransferase activity,91 and the competition with p65 for thecatalytic subunit of protein kinase A.92

    Proteasome Inhibitors

    The 26S proteasome is a large (1,5002,000 kDa) multicatalytic enzyme complexpresent in the nucleus and cytoplasm of eukaryotic cells, whose essential function isto degrade proteins.93,94 It mediates the degradation of several key cell cycle regu-lators and apoptosis-inducing factors such as p53, Bcl-2, p21, p27, and cyclins A, B,D, and E.95101

    The 26S proteasome regulates NF- k B activation in that it is responsible for Ik B adegradation after its phosphorylation and ubiquitinylation. Therapies aiming to sup-press proteasome activity are thus worthy of interest, as they attempt to inhibit theNF- k B-driven expression of antiapoptotic and proinflammatory gene products. Theactivities of several proteasome inhibitors, such as peptide aldehydes (MG132and PSI),102 lactacystine,103 peptide boronic acids,104 vinyl sulfone tripeptides,105,106and natural products such as eponemycin and epoxomycin,107,108 have thus been thor-oughly examined. Among those substances, the most promising are peptide boronicacids, with the compound bortezomib (Velcade, PS-341) presenting death-inducingproperties in multiple myeloma, lung cancer,109 human prostate cancer, and squa-mous cell carcinoma xenografts in mice as well as in grafted mouse mammarytumors.104,110 Antiproliferative and antiproteolytic properties of Bortezomib wereassessed against 60 cell lines derived from various human tumors in a National Can-cer Institute study.104 Moreover, Bortezomib overcomes in vitro multicellular drugresistance and sensitizes cancer cells to tumoricidal drugs.111,112 Bortezomib hassuccessfully entered clinical trials and seems efficient in solid tumors as well as inhematologic malignancies.

    Mesalamine

    Mesalamine is an aminosalicylate compound inhibiting IL-1-induced NF-k Btranscription without modifying either Ik B a degradation or NF- k B nuclear translo-cation and DNA binding. In this case, prevention of gene expression is due to theinhibition of IL-1-driven p65 phosphorylation.113

    Oligonucleotides

    Two types of oligonucleotides have been studied to prevent NF- k B activation: (a)antisense oligonucleotides directed against the p50 subunit reduce IgM and IgG syn-thesis in B cells,114 whereas use of the same method with p65 leads to in vitro inhi-bition of cell adhesion molecules or in vivo blockade of tumor growth in nude miceand prolongs allograft and xenograft survival;115117 (b) decoy oligonucleotidesbinding to transcription factors and thereby preventing promoter activation impairthe expression of several NF- k B target genes such as IL-1, IL-6, ICAM-1, andVCAM.118121 This approach leads to in vivo diminution of inflammatory signs in arat model of rheumatoid arthritis.122

  • 8 ANNALS NEW YORK ACADEMY OF SCIENCES

    Peptides

    Cell-penetrating peptides interfering with proteinprotein interactions also leadto NF- k B function impairment. Peptides constructed with the NF-k B nuclear local-ization sequence (NLS), such as SN50, inhibit NF-k B nuclear translocation trig-gered by lipopolysaccharide and TNF- a .123,124 However, this effect does not seemto be specific to NF- k B, because a peptide based on p50 NLS impairs the nuclearimport of AP-1, NFAT, and STAT-1, whose NLS are different from the p50 NLS.125

    Development of a peptide containing the IKKg -binding motif (NEMO bindingdomain [NBD]) of IKK a and IKK b has also been reported, and this peptide inhibitsTNF- a -induced NF- k B activation.126 This peptide has been tested in various animalmodels of inflammation and seems to be a potent anti-inflammatory agent.

    CONCLUSIONS

    NF- k B and its target genes are potent antiapoptotic and proinflammatory media-tors and are thus involved in various pathologies such as chronic inflammatory dis-eases and cancers. Inhibition of NF-k B activation is a very promising therapeuticapproach to fight those pathologies. Some inhibitors are already potent NF-k B mod-ulators in clinical use, and others remain perfectible benchtop compounds. Never-theless, a better understanding of the different steps leading to NF-k B transcriptionalactivation in different cancer types will permit increased accuracy in the synthesis ofvarious inhibitors, allowing precise targeting of the chosen step. So, the best is yetto come.

    ACKNOWLEDGMENTS

    Research at the laboratory of M.D. is supported by the Fondation de RechercheCancer et Sang, by the Recherches Scientifiques Luxembourg association, byTlvie grants, and by the Een Herz fir kriibskrank Kanner association.

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