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Biochemical Pharmacology (v.72, #9)
Can NF-κB be a target for novel and efficient anti-cancer agents?
by Sabine Olivier; Pierre Robe; Vincent Bours (pp. 1054-1068).
Since the discovery of the NF-κB transcription factor in 1986 and the cloning of the genes coding for NF-κB and IκB proteins, many studies demonstrated that this transcription factor can, in most cases, protect transformed cells from apoptosis and therefore participate in the onset or progression of many human cancers. Molecular studies demonstrated that ancient widely used drugs, known for their chemopreventive or therapeutic activities against human cancers, inhibit NF-κB, usually among other biological effects. It is therefore considered that the anti-cancer activities of NSAIDs (non-steroidal anti-inflammatory drugs) or glucocorticoids are probably partially related to the inhibition of NF-κB and new clinical trials are being initiated with old compounds such as sulfasalazine. In parallel, many companies have developed novel agents acting on the NF-κB pathway: some of these agents are supposed to be NF-κB specific (i.e. IKK inhibitors) while others have wide-range biological activities (i.e. proteasome inhibitors). Today, the most significant clinical data have been obtained with bortezomib, a proteasome inhibitor, for the treatment of multiple myeloma. This review discusses the preclinical and clinical data obtained with these various drugs and their putative future developments.
Keywords: Cancer; NF-κB; Chemotherapy; Apoptosis; Proteasome; IKK
Deregulated NF-κB activity in haematological malignancies
by Aurore Keutgens; Isabelle Robert; Patrick Viatour; Alain Chariot (pp. 1069-1080).
The NF-κB family of transcription factors plays key roles in the control of cell proliferation and apoptosis. Constitutive NF-κB activation is a common feature for most haematological malignancies and is therefore believed to be a crucial event for enhanced proliferation and survival of these malignant cells. In this review, we will describe the molecular mechanisms underlying NF-κB deregulation in haematological malignancies and will highlight what is still unclear in this field, 20 years after the discovery of this transcription factor.
Keywords: Abbreviations; ABC; activated B-cell-like; ALCL; anaplastic large cell lymphoma; ALL; acute lymphoblastic leukaemia; AML; acute myeloid leukaemia; BAFF; B cell-activating factor; BCL-2; B-cell lymphoma 2; B-CLL; B-cell chronic lymphocytic leukemia; BCR; B-cell receptor; Blk; B-lymphoid kinase; Btk; Bruton's tyrosine kinase; CARD11; caspase recruitment domain-containing protein 11; c-IAP2; cellular inhibitor of apoptosis 2; CLL; chronic lymphocytic leukaemia; CML; chronic myeloid leukaemia; CTCL; cutaneous T-cell lymphoma cell line; DLBCL; diffuse large B-cell lymphoma; EBV; Epstein-Barr virus; FL; follicular lymphoma; GCB; germinal center-B-like; HD; Hodgkin's disease; HSC; hematopoetic stem cell; HTLV-1; human T-cell leukaemia virus type 1; IκB; IkappaB; IKK; IκB kinase; IL-1; interleukine 1; LMP-1; EBV-encoded protein latent membrane protein 1; LSC; leukemic stem cell; LT-βR; lymphotoxin-β receptor; MALT; mucosal-associated lymphoid tissue; MDS; myelodysplastic syndrome; MLBCL; mediastinal large B-cell lymphoma; NEMO; NF-κB essential modulator; NF-κB; nuclear factor-kappa B; NHL; non-Hodgkin's lymphoma; NIK; NF-κB-activating kinase; PCD; programmed cell death; PKC; protein kinase C; RANK; receptor activator of nuclear factor-kappaB; Rev-T; reticuloendotheliosis virus strain T; RHD; rel homology domain; RIP; receptor interacting protein; RS; Reed–Sternberg; SLPI; secretory leukocyte protease inhibitor; SODD; silencer of death domain; STAT5; signal transducers and activators of transcription; Syk; spleen tyrosine kinase; TAK; TGFβ-activated protein kinase; TCR; T-cell receptor; TNF; tumour necrosis factor; TNF-R; TNF-receptor; TRADD; TNF-receptor-associated death domain protein; TRAF; TNF receptor-associated factor; Ub; Ubiquitination; ZAP70; ζchain-associated protein kinase of 70; kDaNF-κB; IκB; IKK; p100; BCL-3; Lymphoma; Leukemia; Hodgkin disease
Extending the nuclear roles of IκB kinase subunits
by Geoffrey Gloire; Emmanuel Dejardin; Jacques Piette (pp. 1081-1089).
The transcription factor NF-κB plays a key role in a wide variety of cellular processes such as innate and adaptive immunity, cellular proliferation, apoptosis and development. In unstimulated cells, NF-κB is sequestered in the cytoplasm through its tight association with inhibitory proteins called IκBs, comprising notably IκBα. A key step in NF-κB activation is the phosphorylation of IκBα by the so-called IκB kinase (IKK) complex, which targets the inhibitory protein for proteasomal degradation and allows the freed NF-κB to enter the nucleus where it can transactivate its target genes. The IKK complex is composed of two catalytic subunits called IKKα and IKKβ, and a regulatory subunit called NEMO/IKKγ. Despite their key role in mediating IκBα phosphorylation in the cytoplasm, recent works have provided evidence that IKK subunits also translocate into the nucleus to regulate NF-κB-dependent and -independent gene expression, paving the way of a novel and exciting field of research. In this review, we will describe the current knowledge in that research area.
Keywords: Abbreviations; ATM; atexia telengiactasia mutated; CBP; CREB binding protein; COX-2; cyclooxygenase-2; EGF; epidermal growth factor; ELKS; glutamic acid (E), leucine (L), lysine (K) and serine (S); GADD45β; growth arrest and DNA damage-inducing protein 45β; ICAM-1; intercellular adhesion molecule-1; IκB; inhibitor of κB; IKK; IκB kinase; IL-1, -2, -6, -8; interleukin-1, -2, -6, -8; iNOS; inducible nitric oxide synthase; MCP-1; monocyte chemoattractant protein-1; MEF; mouse embryonic fibroblast; MHC; major histocompatibility complex; MIP-1α; macrophage inflammatory protein-1α; NF-κB; nuclear factor-κB; PIDD; p53-induced protein with a death domain; SMRT; silencing mediator for retinoic acid and thyroid hormone receptor; TNFα; tumor necrosis factorα; VCAM-1; vascular cell adhesion molecule-1; XIAP-1; X chromosome-linked IAPNF-κB; IKK; Inflammation; Cytokines; Nucleus; DNA damage
Mechanisms of crosstalk between TNF-induced NF-κB and JNK activation in hepatocytes
by Andy Wullaert; Karen Heyninck; Rudi Beyaert (pp. 1090-1101).
Hepatocyte cell death is a universal feature of inflammatory liver diseases. The observation that mice deficient in the activation of nuclear factor-κB (NF-κB) are not viable because of excessive hepatocyte apoptosis induced by tumor necrosis factor (TNF) made it crystal-clear that NF-κB plays a central role in protecting hepatocytes against TNF-induced cell death. Also during TNF-mediated liver injury, NF-κB was shown to have an essential anti-apoptotic effect, underscoring the therapeutic importance of understanding its underlying molecular mechanisms. For a long time, the ability of NF-κB to induce the expression of a variety of anti-apoptotic proteins was thought to be solely responsible for its cytoprotective effects. However, during the past few years it has become clear that NF-κB-mediated inhibition of cell death also involves attenuating TNF-induced activation of c-Jun activating kinase (JNK). Whereas transient activation of JNK upon TNF treatment is associated with cellular survival, prolonged JNK activation contributes to cell death. Several studies have shown that NF-κB activation inhibits the sustained phase of TNF-induced JNK activation and thus protects cells against TNF cytotoxicity. In this review, we will discuss the various mechanisms by which NF-κB activation blunts TNF-induced JNK activation, including the induction of JNK inhibitory proteins and controlling the levels of reactive oxygen species (ROS). Moreover, because the cytoprotective effects of NF-κB activation are particularly important in liver physiology, we will put each of these JNK-inhibitory mechanisms into a ‘hepatic perspective’ by discussing their role in various mouse models of TNF-mediated liver injury.
Keywords: NF-κB; JNK; Apoptosis; Liver; TNF; Inflammation
Toll-like receptors: From the discovery of NFκB to new insights into transcriptional regulations in innate immunity
by Sarah L. Doyle; Luke A.J. O’Neill (pp. 1102-1113).
Toll-like receptors (TLRs) are key components of the innate immune system, functioning as pattern recognition receptors that recognise a wide range of microbial pathogens. TLRs represent a primary line of defence against invading pathogens in mammals, plants and insects. Recognition of microbial components by TLRs triggers a cascade of cellular signals that culminates in the activation of NFκB which leads to inflammatory gene expression and clearance of the infectious agent. The history of NFκB began with the TLR4 ligand lipopolysaccharide (LPS), a component of the cell wall of Gram-negative bacteria, since this was the stimulus first used to activate NFκB in pre-B-cells. However, since those early days it has been a circuitous route, made possible by drawing on information provided by many different fields, that has led us not only to the discovery of TLRs but also to an understanding of the complex pathways that lead from TLR ligation to NFκB activation. In this review we will summarize the current knowledge of TLR-mediated NFκB activation, and also the recent discoveries that subtle differences in κB binding sequences and NFκB dimer formation result in specific gene expression profiles.
Keywords: Toll-like receptors; NF-κB; Innate immunity
Keeping up NF-κB appearances: Epigenetic control of immunity or inflammation-triggered epigenetics
by Wim Vanden Berghe; ’Matladi N. Ndlovu; Ruben Hoya-Arias; Nathalie Dijsselbloem; Sarah Gerlo; Guy Haegeman (pp. 1114-1131).
Controlled expression of cytokine genes is an essential component of an immune response and is crucial for homeostasis. In order to generate an appropriate response to an infectious condition, the type of cytokine, as well as the cell type, dose range and the kinetics of its expression are of critical importance. The nuclear factor-κB (NF-κB) family of transcription factors has a crucial role in rapid responses to stress and pathogens (innate immunity), as well as in development and differentiation of immune cells (acquired immunity). Although quite a number of genes contain NF-κB-responsive elements in their regulatory regions, their expression pattern can significantly vary from both a kinetic and quantitative point of view, reflecting the impact of environmental and differentiative cues. At the transcription level, selectivity is conferred by the expression of specific NF-κB subunits and their respective posttranslational modifications, and by combinatorial interactions between NF-κB and other transcription factors and coactivators, that form specific enhanceosome complexes in association with particular promoters. These enhanceosome complexes represent another level of signaling integration, whereby the activities of multiple upstream pathways converge to impress a distinct pattern of gene expression upon the NF-κB-dependent transcriptional network. Today, several pieces of evidence suggest that the chromatin structure and epigenetic settings are the ultimate integration sites of both environmental and differentiative inputs, determining proper expression of each NF-κB-dependent gene. We will therefore discuss in this review the multilayered interplay of NF-κB signaling and epigenome dynamics, in achieving appropriate gene expression responses and transcriptional activity.
Keywords: NF-κB; Cofactor; Histone; Chromatin; Epigenetics; DNA methylation
NF-κB activation by double-strand breaks
by Yvette Habraken; Jacques Piette (pp. 1132-1141).
Cellular response to DNA damage is complex and relies on the simultaneous activation of different networks. It involves DNA damage recognition, repair, and induction of signalling cascades leading to cell cycle checkpoint activation, apoptosis, and stress related responses. The fate of damaged cells depends on the balance between pro- and antiapoptotic signals. In this decisive life or death choice, the transcription factor NF-κB has emerged as a prosurvival actor in most cell types. As corollary, it appears to be associated with tumorigenic process and resistance to therapeutic strategies as it protects cancerous cells from death. In this review, we will focus on NF-κB activation by double-strand breaks inducing agents, such as ionizing radiation and DNA topoisomerase I and II inhibitors routinely used in cancer therapy. Coinciding with the 20th anniversary of the NF-κB discovery, major steps of the DSB-triggered cascade have been recently identified. Two parallel cascades are necessary for NF-κB activation. The first one depends on ATM (activated by double-strand breaks) and the second on PIDD (activated by an unknown stress signal). The phosphorylation of NEMO by ATM is the point of convergence of these two cascades. The identification of ATM/NEMO complex as the long searched “nuclear to cytoplasm� signal leading to IKK activation is also a major piece of the puzzle. The knowledge of the precise steps leading to DSB-initiated NF-κB activation will allow the development of specific blocking compounds reducing its prosurvival function.
Keywords: Abbreviations; AT; Ataxia Telangiectasia; ATLD; Ataxia Telangiectasia-Like Disease; ATM; Ataxia Telangiectasia Mutated; ATM; P; phosphorylated ATM; ATR; ATM- and Rad 3-related kinase; CC; coiled-coil domain; CPT; camptothecin; DNA-PK; DNA–protein kinase; Dox; Doxorubicin; DSB; double-strand breaks; HED; hypohydrotic ectodermal dysplasia; IκB; inhibitor of κB; IKK; IκB kinase; IR; ionizing radiation; NBS; Nijmegen Breakage Syndrome; NCS; neocarzinostatin; NEMO; NF-κB essential modulator; NF-κB; nuclear factor-κB; MRN; Mre11/Rad50/NBS; PIDD; p53-inducible death domain-containing protein; RIP; receptor-interacting protein; ROS; reactive oxygen species; SSB; single-strand breaks; ZF; zinc fingerNF-κB; Double-strand breaks; Cellular signalling; ATM; DNA topoisomerase inhibitors; Ionizing radiation
NF-κB in solid tumors
by Francesco Pacifico; Antonio Leonardi (pp. 1142-1152).
Cancer is a multistep process during which cells acquire genetic alterations that drive the progressive transformation of normal cells into highly malignant cells. Self-sufficiency in growth, insensitivity to anti-growth signals, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, tissue invasion and metastasis, are signatures of transformed cells. NF-κB is a key actor in tumorigenesis given its ability to control the expression and the function of a number of genes involved in these processes. Indeed, constitutive activation of NF-κB is a common feature of many human tumors, while its sustained activation during inflammation predisposes normal cells to neoplastic transformation. Since suppression of NF-κB has been shown to inhibit oncogenic potential of transformed cells, targeting it should be effective in the prevention and treatment of cancer.
Keywords: Abbreviations; c-FLIP; cellular FADD-like interleukin 1beta converting enzyme inhibitory protein; CDK; cyclin dependent kinase; COX; cycloxygenase; CXCR; chemokine receptor; ELAM; endothelial cell leukocyte adhesion molecule; GADD; growth arrest and DNA damage; IAP; inhibitor of apoptosis; ICAM; intercellular adhesion molecule; IKK; IκB kinase; IL; interleukin; IκB; inhibitor of NF-κB; JNK; Jun N-terminal kinase; NEMO; NF-κB essential modulator; NF-κB; nuclear factor-kappa B; PTEN; phosphatase and tensin homologue; ROS; reactive oxygen species; TNF; tumor necrosis factor; TRAIL; TNF-related apoptosis-inducing ligand; VCAM; vascular cell adhesion moleculeNF-κB; Cancer; Apoptosis; Inflammation; Cytokines; Therapeutic targets
NF-κB and inflammation in genetic disease
by Hélène Sebban; Gilles Courtois (pp. 1153-1160).
By responding to pro-inflammatory cytokines, such as IL-1β and TNF-α, and controlling itself the expression of numerous mediators of inflammation, NF-κB plays a pivotal role in controlling the proper sequence of events characterizing the inflammation process. Although excessive NF-κB activation is often associated with inflammatory signs in many different tissues, impaired NF-κB activation can also generate inflammation. This is the case in humans suffering from the genetic disease incontinentia pigmenti that exhibit severe skin inflammation. Identifying the molecular basis of this pathology, mutations affecting the gene coding for NEMO, has allowed production of mouse models for investigating the disease. Their characterization supports the view that a very tight positive and negative regulation of the NF-κB signaling pathway is required in vivo to ensure not only a fine-tuned response to injury or infection but also to maintain tissue homeostasis.
Keywords: Abbreviations; CFTR; cystic fibrosis transmembrane conductance regulator; EDA-ID; anhidrotic ectodermal dysplasia with immunodeficiency; IκB; IkappaB; IKK; IκB kinase; IL-1; interleukin-1; IL-1-R; interleukin-1-receptor; IL-1RacP; IL-1 receptor accessory protein; iNOS; inducible nitric oxide synthase; IP; incontinentia pigmenti; IRAK; IL-1 receptor associated kinase; LPS; lipopolysaccharide; NEMO; NF-κB essential modulator; NF-κB; nuclear factor-kappa B; NOD; nucleotide-binding oligomerization domain; RIP; receptor interacting protein; TAB; TAK1-binding protein; TAK; TGF-β activated kinase; TIR; Toll/IL-1 receptor domain; TIRAP; TIR domain-containing adaptor protein; TLR; Toll-like receptor; TNF; tumor necrosis factor; TNF-R; TNF-receptor; TRADD; TNF-receptor-associated death domain protein; TRAF; TNF receptor-associated factor; TRAM; TRIF-related adapter molecule; TRIF; TIR-domain-containing adapter-inducing IFN-βInflammation; NF-κB; Incontinentia pigmenti
The alternative NF-κB pathway from biochemistry to biology: Pitfalls and promises for future drug development
by Emmanuel Dejardin (pp. 1161-1179).
The past two decades have led to a tremendous work on the transcription factor NF-κB and its molecular mechanisms of activation. The nuclear translocation of NF-κB is controlled by two main pathways: the classical and the alternative NF-κB pathways. The classical NF-κB pathway activates the IKK complex that controls the inducible degradation of most IκB family members that are IκBα, IκBβ, IκBɛ and p105. The alternative NF-κB pathway induces p100 processing and p52 generation through the activation of at least two kinases, which are NIK and IKKα. Genetic studies have shown that IKKγ is dispensable for the alternative pathway, which suggests the existence of an alternative IKKα-containing complex. It is noteworthy that activation of particular p52 heterodimers like p52/RelB requires solely the alternative pathway while activation of p52/p65 or p52/c-Rel involves a “hybrid pathway�. Among others, LTβR, BAFF-R, CD40 and RANK have the ability to induce the alternative pathway. The latter plays some roles in biological functions controlled by these receptors, which are the development of secondary lymphoid organs, the proliferation, survival and maturation of B cell, and the osteoclastogenesis. Exacerbated activation of the alternative pathway is potentially associated to a wide range of disorders like rheumatoid arthritis, ulcerative colitis or B cell lymphomas. Therefore, inhibitors of the alternative pathway could be valuable tools for the treatment of inflammatory disorders and cancers.
Keywords: Abbreviations; BAFF; B cell activating factor belonging to the TNF family; BLC; B lymphocyte chemoattractant; ELC; Epstein-Barr virus induced molecule 1 ligand chemokine; FDC; follicular dendritic cells; FL B cells; follicular B cells; GC; germinal center; IKK; inhibitor kappa B kinase; KO; knock out; LIGHT; homologous to lymphotoxin exhibits inducible expression; and competes with HSV glycoprotein D for Herpes virus entry mediator; a receptor expressed by T lymphocytes; LMP1; latent membrane protein 1; LN; lymph node; LTβR; lymphotoxin-beta receptor; MALT; mucosa-associated lymphoid tissue; MEFs; mouse embryonic fibroblasts; MZB; marginal zone B cell; NALT; nasal-associated lymphoid tissue; NF-κB; nuclear factor-kappa B; NIK; NF-κB-inducing kinase; PP; Peyer's patch; RANK; receptor activator of NF-κB; RANKL; RANK ligand; TNF; tumour necrosis factor; TNFR; TNF receptor; TRAF; TNF receptor associated factor; SLC; secondary lymphoid tissue chemokine; SLO; secondary lymphoid organ; TLO; tertiary lymphoid organ; wt; wild typeAlternative pathway; NIK; IKK; NF-κB; p100/p52; Inflammation
NF-κB functions in the nervous system: From development to disease
by Sylvie Mémet (pp. 1180-1195).
The transcription factor nuclear factor-κB (NF-κB) is an ubiquitously expressed dimeric molecule with post-translationally regulated activity. Its role in the immune system and host defense has been well characterized over the last two decades. In contrast, our understanding of the function of this transcription factor in the nervous system (NS) is only emerging. Given their cytoplasmic retention and nuclear translocation upon stimulus, NF-κB members are likely to exert an important role in transduction of signals from synaptic terminals to nucleus, to initiate transcriptional responses. This report describes recent findings deciphering the diverse functions of NF-κB in NS development and activity, which range from the control of cell growth, survival and inflammatory response to synaptic plasticity, behavior and cognition. Particular attention is given to the specific roles of NF-κB in the various cells of the NS, e.g. neurons and glia. Current knowledge of the contribution of NF-κB to several neurodegenerative disorders, such as Alzheimer's, Parkinson's and Huntington's diseases is also summarized.
Keywords: NF-κB; Transcription factor; Central and peripheral nervous system; Development; Neurons and glia; Neurodegenerative diseases
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