Definition of i-kappa b proteins in the Definitions.net dictionary. Meaning of i-kappa b proteins. What does i-kappa b proteins mean? Information and translations of i-kappa b proteins in the most comprehensive dictionary definitions resource on the web.
The ability of a cell to combat an intracellular pathogen requires a mechanism to recognize the threat and elicit a transcriptional response against it. In the context of virus infection, the cell must take measures to inhibit viral replication, meanwhile, convey warning signals to neighboring cells of the imminent threat. This immune response is predominantly mediated by the production of cytokines, notably, interferon beta (IFNβ). IFNβ signaling results in the transcriptional induction of over one hundred antiviral gene products whose timely expression renders infected cells more capable of inhibiting virus replication, while providing the uninfected cells with the reinforcements to generate a less permissive cellular environment. Induction of IFNβ and many aspects of the antiviral response pivot on the function of the IKK and IKK-related kinases. Despite sharing high levels of homology and some degree of functional redundancy, the classic IKK kinases: IKKα and IKKβ, and the IKK-related kinases:
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The transcription factor nuclear factor (NF)-κB plays a pivotal role in the regulation of innate immunity, stress responses, inflammation, and the inhibition of apoptosis 1,2. The activity of NF-κB is tightly regulated by cytokines and other external stimuli. In most cell types, NF-κB is present as a heterodimer comprising 50-kD (p50) and 65-kD (p65) subunits and is sequestered in the cytoplasm by a member of the inhibitor of κB (IκB) family of inhibitory proteins. NF-κB activation requires the degradation of IκB proteins, and the mechanisms of IκB degradation and subsequent NF-κB activation have been the subject of intense investigation 3. Those studies have revealed two important classes of kinase involved in this pathway: mitogen-activated protein kinase kinase kinase (MAP3K) and its downstream target, IκB kinase (IKK) 4,5. NF-κB-inducing kinase (NIK) is structurally related to MAP3K and has been identified as a TNFR-associated factor (TRAF)2-interacting protein 6. On the basis of ...
The early host response to viral infection is regulated by the type I interferons (IFNα/β), which are induced after detection of virus-specific products. The subsequent transcriptional response is mediated via the Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway, which controls transcription of a range of interferon-stimulated genes (ISGs). The IKK-related kinases TBK and IKKε (an inhibitor of nuclear factor κB kinase) are also integral components of the IFNβ pathway. However, tenOever et al. reveal that, although mice deficient in IKKε are susceptible to viral infection, this susceptibility is not because of a loss of IFNβ expression. Rather, the deficiency resulted from an unanticipated downstream effect in which IKKε prevents homodimerization of STAT-1 by its phosphorylation. Instead, STAT-1 was incorporated into a heterotrimeric complex transcribing a distinct set of ISGs.. B. R. tenOever, S.-L. Ng, M. A. Chua, S. M. McWhirter, A. García-Sastre, T. ...
by Juliane In 2003 these two fish swam across the pacific ocean to find Nemo: Five years earlier, S. Yamaoka and colleagues also set out to find Nemo, the NF-kappaB essential modifier. NF-kappaB is a very famous transcription factor, which is present in all eukaryotic cells and can be activated by a large number of […]. ...
Processing of the NF-kappa B2 precursor p100 to the mature p52 subunit is regulated via a unique pathway. NF-kappa B-inducing kinase (NIK) induces I kappa B kinase alpha (IKK alpha)-mediated phosphorylation of specific serine residues in the C-terminal domain of p100, leading to recruitment of the S …
It has quickly become clear that the RNA helicase RIG-I pathway plays an essential role in the sensing of incoming virus infection and directly relays regulatory signals to the host antiviral response. The adapter molecule providing a link between RIG-I sensing of incoming viral RNA and downstream activation events was recently elucidated; four independent groups used high-throughput screening and/or database search analyses to identify the new signaling component, which has alternatively been termed MAVS/IPS-1-1/VISA/Cardif (20, 29, 35, 40) and is termed K1271 in this study. The fact that MAVS/IPS-1-1/VISA/Cardif localizes to the mitochondrial membrane suggests linkage among recognition of viral infection, the development of innate immunity, and mitochondrial function (35). The IKK-related kinases TBK1 and IKKε are critical downstream components of the activation of the interferon antiviral response through their ability to phosphorylate the C-terminal domains of IRF-3 and IRF-7 (13, 28, 36). ...
Impaired generation of immature NEMO-deficient Igλ+ B cells in the absence of rearrangements at Igk loci. (a) BM cells from iEκT homozygous mice (iEκT/T)-
Mouse anti Human IKK epsilon antibody recognizes the inhibitor of nuclear factor kappa-B kinase subunit epsilon, also known as I-kappa-B k
Sigma-Aldrich offers abstracts and full-text articles by [Tony T Huang, Shelly M Wuerzberger-Davis, Zhao-Hui Wu, Shigeki Miyamoto].
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Supplement Figure S1 Expression of mature miR-15 family members in gastrointestinal cancers. Supplement Figure S2 Establishment of stable cell lines highly expressing miR-195. Supplement Figure S3 MiR-195 inhibited Huh-7, SGC-7901 and LOVO cell proliferation in vitro.. Supplement Figure S4 MiR-195 inhibited Huh-7, SGC-7901 and LOVO cell migration and invasion in vitro.. Supplement Figure S5 MiR-195 has no obvious effects on cell growth with matrigel within 40 h after transfection. Supporting Figure S6 No difference between negative control and miR-195 mutant RNA in cell proliferation and colony formation.. Supporting Figure S7 No difference between negative control and miR-195 mutant RNA in cell migration and invasion.. Supporting Figure S8 Western blotting assays of IKKα or TAB3 expression. Supporting Table S1 Primer sequences for constructs and DNA copy number assay. Supporting Table S2 The sequences of siRNA used in this study. Supporting Table S3 Roche probes used in this study. Supporting ...
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The activation of NF-κB is mainly by two signaling pathways - the canonical pathway (which is the classical pathway) and the non-canonical pathway (which is also called the alternative pathway). Lets discuss about each of the pathway in detail. But before going ahead, it is important to note the common regulatory step of both the cascades is the activation of IκBkinase (IKK) complex. In unstimulated cells, the inhibitor, NF-κB proteins are bound to IκB protein that maintains NF-κB in an inactive state. Hence, when IκB is activated i.e.; phosphorylated, it gets ubiquitinated and is degraded by proteasome. The IKK complex consists of kinase subunits that are catalytic (IKKα and/or IKKβ) and non-enzymatic protein that is regulatory in nature - known as NEMO which stands for NF-κB essential modulator, also known as IKKγ. ...
Ikk-alfa (Inhibitor of kappa B kinase alfa) codes for an intracellular regulator of NF-kB-signaling. NF-kB (Nuclear factor-kappa B) is a homo- or heterodimeric transcription factor involved in many biological processes including regulation of a response to inflammation and of decisions of cell behaviour during development (Mikkola et al, 2003). NF-kB is kept inactive by rendering it to cytoplasm by masking the nuclear localization signal by Inhibitor of kB (IkB) isoforms. Phosphorylation of these inhibitors by IKK-complex leads to release of NF-kB-dimers which are now capable to enter the nucleus. IKK-complex consists of three subunits, alfa, beta and gamma. IKK-alfa and IKK-beta subunits harbor kinase activity while the IKK-gamma subunit (also called NEMO) has a regulatory function. The kinase activity, leading to expression of NF-kB target genes, is triggered by many factors, e.g. interleukins and tumor necrosis factors (TNFs). These include EDA, a TNF-family ligand, that regulates the ...
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TRAF6 is a signal transducer that activates IkappaB kinase (IKK) and Jun amino-terminal kinase (JNK) in response to pro-inflammatory mediators such as interleukin-1 (IL-1) and lipopolysaccharides (LPS). IKK activation by TRAF6 requires two intermediary factors, TRAF6-regulated IKK activator 1 (TRIKA …
Electrophysiological and psychophysical responses to a low-intensity probe sound have a tendency to be suppressed with a preceding high-intensity adaptor sound. should present enhanced replies to low-intensity deviant noises provided among high-intensity criteria. Unlike this prediction, deviant responses were just improved when the deviants and standards differed in frequency. The results could possibly be explained using a model lets assume that IC neurons integrate over multiple frequency-tuned stations which version takes place within each route independently. We utilized an version paradigm with multiple repeated adaptors to gauge the tuning widths of the adaption stations with regards to the neurons general tuning widths. Version identifies the suppression from the brains response to or frequently occurring sensory stimuli repeatedly. Adaptation continues to be discovered from single-neuron to macroscopic people responses and it is ubiquitous across sensory systems1,2. Even so, its ...
Simultaneous CRISPR/Cas9-mediated knockout of IKBKA (IKK1) and IKBKB (IKK2) resulted in cells highly sensitized for programmed cell death (apoptotic/necroptotic) after exposure to tumor necrosis factor (TNF)-α. This effect was not observable in single knockouts for either IKK1 or IKK2. Targeting of IKK1 and IKK2 simultaneously, preferably on the genome level, therefore opens up new therapeutic avenues to tackle proliferative disorders such as cancer. Hence, the present methods and compositions provide a means for the selective induction of apoptosis in cells associated with a proliferative disorder, such as tumor cells. Commercial Opportunities Novel gene therapy and a novel drug screening concept are offered for licensing. Competitive Advantages. ...
While growth factor-independent signaling and proliferation are well-established hallmarks of cancer, little is known regarding growth factor-independent changes in gene expression which occur downstream from oncogenes. The PI3K pathway is one of the most commonly misregulated signaling pathways in human cancers. Here, MCF10A cells expressing the two most common PI3K mutations, PIK3CA E545K and H1047R, were used to identify the repertoire of genes altered by oncogenic PI3K mutations following growth factor deprivation. This gene set most closely correlated with gene signatures from claudin-low and basal-like breast tumors, and categorical enrichment analyses suggested that NF-κB target genes were dramatically upregulated by these mutations. An IKKα inhibitor was used to identify the subset of PI3K-driven genes that is NF-κB dependent. Interestingly, virtually all of these NF-κB dependent genes were secreted proteins, suggesting a paracrine role for this gene set. Among these genes was IL-6, ...
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Das Schicksal aktivierter T-Zellen wird durch eine Vielzahl NF-kappaB regulierter Ziel-Gene bestimmt, wobei aktivierende und deaktivierende Signale für die Ausbalancierung einer adäquaten T-Zell Antwort benötigt werden. Im Rahmen dieser Arbeit konnte gezeigt werden, dass die negativ-regulatorische Modulierung des Carma1-Bcl10-Malt1 (CBM)-Proteinkomplexes für die Steuerung der NF-kappaB Aktivität in T-Zellen von großer Bedeutung ist. Überraschenderweise ist die Bildung des CBM-Komplexes abhängig von IKKbeta, einer Kinase, die zuvor ausschließlich mit CBM-nachgelagerten Effektorfunktionen in Verbindung gebracht wurde. IKKbeta übernimmt eine duale Funktion bei der Regulation des CBM-Komplexes: Obwohl IKKbeta zunächst für die Bildung des CBM-Komplexes benötigt wird, führt die Phosphorylierung der CBM-Komplexkomponente Bcl10 durch IKKbeta bereits kurze Zeit nach Beginn der T-Zell Aktivierung zu einer Dämpfung der Signalübertragung. Biochemische Analysen zeigen, dass die ...
Upon binding DNA, cGAS produces cGAMP that binds to and activates the adaptor protein STING, which then activates the kinases IKK and TBK1 to induce interferons and other cytokines(2-6 ...
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TY - JOUR. T1 - Nuclear Role of IκB Kinase-γ/NF-κB Essential Modulator (IKKγ/NEMO) in NF-κB-dependent Gene Expression. AU - Verma, Udit N.. AU - Yamamoto, Yumi. AU - Prajapati, Shashi. AU - Gaynor, Richard B.. PY - 2004/1/30. Y1 - 2004/1/30. N2 - The IκB kinase (IKK) complex, which is composed of the two kinases IKKα and IKKβ and the regulatory subunit IKKγ/nuclear factor-κB (NF-κB) essential modulator (NEMO), is important in the cytokine-induced activation of the NF-κB pathway. In addition to modulation of IKK activity, the NF-κB pathway is also regulated by other processes, including the nucleocytoplasmic shuttling of various components of this pathway and the post-translational modification of factors bound to NF-κB-dependent promoters. In this study, we explored the role of the nucleocytoplasmic shuttling of components of the IKK complex in the regulation of the NF-κB pathway. IKKγ/NEMO was demonstrated to shuttle between the cytoplasm and the nucleus and to interact with the ...
Cardiomyocyte-specific I kappa B kinase (IKK)/NF-kappa B activation induces reversible inflammatory cardiomyopathy and heart ...
Nitrosourea represents one of the most active classes of chemotherapeutic alkylating agents for metastatic melanoma. Treatment with nitrosoureas caused severe systemic side effects which hamper its clinical use. Here, we provide pharmacological evidence that reactive oxygen species (ROS) induction and IKKβ inhibition cooperatively enhance nitrosourea-induced cytotoxicity in melanoma cells. We identified SC-514 as a ROS-inducing IKKβ inhibitor which enhanced the function of nitrosoureas. Elevated ROS level results in increased DNA crosslink efficiency triggered by nitrosoureas and IKKβ inhibition enhances DNA damage signals and sensitizes nitrosourea-induced cell death. Using xenograft mouse model, we confirm that ROS-inducing IKKβ inhibitor cooperates with nitrosourea to reduce tumor size and malignancy in vivo. Taken together, our results illustrate a new direction in nitrosourea treatment, and reveal that the combination of ROS-inducing IKKβ inhibitors with nitrosoureas can be potentially ...
Innate immune receptor that senses cytoplasmic viral nucleic acids and activates a downstream signaling cascade leading to the production of type I interferons and proinflammatory cytokines. Forms a ribonucleoprotein complex with viral RNAs on which it homooligomerizes to form filaments. The homooligomerization allows the recruitment of RNF135 an E3 ubiquitin-protein ligase that activates and amplifies the RIG-I-mediated antiviral signaling in an RNA length-dependent manner through ubiquitination-dependent and -independent mechanisms (PubMed:28469175, PubMed:31006531). Upon activation, associates with mitochondria antiviral signaling protein (MAVS/IPS1) that activates the IKK-related kinases TBK1 and IKBKE which in turn phosphorylate the interferon regulatory factors IRF3 and IRF7, activating transcription of antiviral immunological genes including the IFN-alpha and IFN-beta interferons (PubMed:28469175, PubMed:31006531). Ligands include 5-triphosphorylated ssRNAs and dsRNAs but also short ...
T cell leukemia virus type 1 (HTLV-1) is a causative factor for adult T cell leukemia and lymphoma (ATLL). HTLV-1 genome encodes a viral transforming protein, T...
The inhibitor of NF-κB (I-κB) kinase (IKK) complex consists of 3 subunits, IKK1, IKK2, and NF-κB essential modulator (NEMO), and is involved in the activation of NF-κB by various stimuli. IKK2 or NEMO constitutive knockout mice die during embryogenesis as a result of massive hepatic apoptosis. Therefore, we examined the role of IKK2 in TNF-induced apoptosis and ischemia/reperfusion (I/R) injury in the liver by using conditional knockout mice. Hepatocyte-specific ablation of IKK2 did not lead to impaired activation of NF-κB or increased apoptosis after TNF-α stimulation whereas conditional NEMO knockout resulted in complete block of NF-κB activation and massive hepatocyte apoptosis. In a model of partial hepatic I/R injury, mice lacking IKK2 in hepatocytes displayed significantly reduced liver necrosis and inflammation than wild-type mice. AS602868, a novel chemical inhibitor of IKK2, protected mice from liver injury due to I/R without sensitizing them toward TNF-induced apoptosis and ...
The IKK complex, isolated from extracts of HeLa cells treated with the proinflammatory cytokine TNF (tumor necrosis factor), phosphorylates two regulatory serine residues at the NH2-termini of the NF-κB inhibitors IκBα and IκBβ (1). This phosphorylation event triggers the polyubiquitination of IκBs followed by their degradation through the 26S proteasome, and thereby leads to NF-κB activation (2). IKK is a large, 900-kD, protein complex that is composed of multiple subunits. Two of these subunits, IKKα and IKKβ, are serine kinases (1, 3-6). Epitope-tagged IKKα and IKKβ, when produced by cell-free translation in reticulocyte lysates or by transient transfection of mammalian cells, are incorporated into the IKK complex, which can be isolated by immunoprecipitation of either IKKα or IKKβ (1, 4). The IκB kinase activity of the entire complex is rapidly stimulated by TNF or interleukin 1 (IL-1), with kinetics matching those of IκBα phosphorylation and degradation (1,4).. Because ...
AKT(Ser473), AKT(Thr308), AKT(Tyr326), AKT1(Thr450), AKT1(Thr72), AKT1(Tyr474), AKT2(Ser474), c-Jun(Ser243), c-Jun(Ser63), c-Jun(Ser73), c-Jun(Thr239), c-Jun(Thr91), c-Jun(Thr93), c-Jun(Tyr170), COX2, Elk1(Ser383), Elk1(Ser389), Elk1(Thr417), ERK1/2, ERK3(Ser189), Fos(Thr232), FosB(Ser27), GAP43(Ser41), GRB2(Ser159), GTPase activating protein(Ser387), IkB-alpha(Ser32/36), IkB-alpha(Tyr42), IkB-beta(Thr19), IkB-epsilon(Ser22), IKK alpha(Thr23), IKK beta(Tyr188), IKK beta(Tyr199), IKK gamma(Ser31), IKK gamma(Ser85), IKKa/b(Ser180/181), IP3KA, IP3KC, JAK1(Tyr1022), JAK2(Tyr1007), JAK2(Tyr221), JNK1/2/3(Thr183/Tyr185), JNKK (MKK4), MAP3K1/MEKK1(Thr1381), MEK1(Ser217), MEK1(Ser221), MEK1(Ser298), MEK1(Thr286), MEK1(Thr291), MEK2(Thr394), NFkB-p100/p52(Ser865), NFkB-p105(Ser927), NFkB-p105/p50(Ser337), NFkB-p105/p50(Ser932), NFkB-p65(Ser536), NFkB-p65(Thr254), p44/42 MAPK(Thr202), p44/42 MAPK(Tyr204), PAK1(Ser204), PAK1(Thr212), PAK1/2(Ser199), PAK1/2/3(Ser141), PAK1/2/3(Thr423/402/421), PAK2(Ser192), ...
IL-17 is linked to increased immunopathology in several viral infections (1-3), but the molecular mechanisms behind its role remain largely undefined. In this study, we demonstrate that IL-17 specifically boosts proinflammatory, but not antiviral, gene expression in human cells infected with RSV or stimulated with the viral mimic poly(I:C). Moreover, we investigate the molecular mechanisms behind the synergistic effect of IL-17 and viral signaling, which at the transcriptional level involves IKKs and transcription factors IRF3 and RelA. It would therefore be interesting to assess whether the IKK inhibitors, which we show interfere with IL-17/poly(I:C) synergistic induction of proinflammatory genes in vitro, could be used to block IL-17-dependent responses in vivo.. IL-17 is known to trigger TNF-α-induced cytokine mRNA stabilization (15). However, in our system, poly(I:C)/IL-17 synergy is independent of TNF-α, as TNF protein is not detectable in HSFs infected with RSV or stimulated with ...
Nuclear factor-κB (NF-κB) has been long considered a master regulator of inflammation and immune responses. Additionally, aberrant NF-κB signaling has been linked with carcinogenesis in many types of cancer. In recent years, the study of NF-κB members in NF-κB unrelated pathways provided novel attractive targets for cancer therapy, specifically linked to particular pathologic responses. Here we review specific functions of IκB kinase complexes (IKKs) and IκBs, which have distinctly tumor promoting or suppressing activities in cancer. Understanding how these proteins are regulated in a tumor-related context will provide new opportunities for drug development ...
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NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells) refers to a protein complex functional in signaling pathways, particularly in response to stress stimuli. There are two signaling pathways leading to the activation of NF-kB signaling, known as the canonical (or classical) pathway, the non-canonical (or alternative) pathway.. In the canonical NF-kB pathway, NF-kB dimers such as p50/RelA are maintained in the cytoplasm by interaction with an independent Inhibitor of NF-kB (IkB) molecule. When the upstream signaling is active, an IkBa kinase (IKK) complex consisting of catalytic kinase subunits IKKa and/or IKKb and the scaffold protein NEMO will be recruited to the cytoplasmic adaptor of certain cell surface receptor and stay activated. Activation of IKK complex will consequently phosphorylate the IkB at two serine residues, which induce the proteasomal degradation of IkB. Released from IkB, NF-kB dimers then translocate into the nucleus and bind with a consensus sequence ...
Transient activation of NF-kappaB through a TAK1/IKK kinase pathway by TGF-beta1 inhibits AP-1/SMAD signaling and apoptosis: implications in liver tumor formation ...
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The IKK complex plays a crucial role in NF-κB activation, making it an appealing target for viruses as a means to block NF-κB-mediated activation of the proinflammatory response (31-33). Other viral proteins target the IKK complex to inhibit NF-κB activation, such as the vaccinia virus B14 protein (34) and the enterovirus 2C protein (35), each of which bind to IKKβ to block IKKβ phosphorylation to inhibit NF-κB activity. In this study, we show that the MC159 protein inhibited three distinct pathways that result in NF-κB activation. MC159 also coimmunoprecipitated with the IKK complex but did not require IKKα or IKKβ to coimmunoprecipitate with IKKγ. We also observed MC159-IKKγ interactions in either MCV-infected cells or cells in which MC159 was expressed by a surrogate virus (21).. The upstream signal transduction pathways triggered by TNF, MyD88, and PMA converge upon IKK (12, 36). Because MC159-inhibited NF-κB triggered through each of these effectors, we speculated that MC159 ...
Protein transduction domains (PTDs), both naturally occurring and synthetic, have been extensively utilized for intracellular delivery of biologically active molecules both in vitro and in vivo. However, most comparisons of transduction efficiency have been performed using fluorescent markers. To compare efficiency of functional protein transduction, a peptide derived from IkB kinase ß (IKKß) that prevents formation of an active IKK complex was used as a biologically active cargo. This peptide, termed NEMO Binding Domain (NBD), is able to block activation of the transcriptional factor NF-κB by IKK, but not basal NF-κB activity. Our results demonstrate that Antp and Tat PTDs were most effective for delivery of NBD for inhibition of NF-kB activation compared to other PTD-NBD in both Hela and 293 cells, however, at higher concentrations (100 µM), the Antp-NBD as well as the FGF-NBD peptide caused significant cellular toxicity. In contrast to the cell culture results, delivery of NBD using 8K
Familial incontinentia pigmenti (IP; MIM 308310) is a genodermatosis that segregates as an X-linked dominant disorder and is usually lethal prenatally in males. In affected females it causes highly variable abnormalities of the skin, hair, nails, teeth, eyes and central nervous system. The prominent skin signs occur in four classic cutaneous stages: perinatal inflammatory vesicles, verrucous patches, a distinctive pattern of hyperpigmentation and dermal scarring. Cells expressing the mutated X chromosome are eliminated selectively around the time of birth, so females with IP exhibit extremely skewed X-inactivation. The reasons for cell death in females and in utero lethality in males are unknown. The locus for IP has been linked genetically to the factor VIII gene in Xq28 (ref. 3). The gene for NEMO (NF-kappaB essential modulator)/IKKgamma (IkappaB kinase-gamma) has been mapped to a position 200 kilobases proximal to the factor VIII locus. NEMO is required for the activation of the transcription ...
Neuroinflammation is an essential defense response to pathogens or injury in the central nervous system, but might also contribute to the pathogenesis of neurological disorders. Astrocytes are glial cells that are implicated in neuroinflammation, but also in brain development and homeostasis. The NF-kappa B transcription factors are key regulators of inflammation that also regulate in cell proliferation, differentiation and survival. Previous studies suggested that NF-kappa B activation in astrocytes might indeed be critical for neuroinflammatory responses and its pathological consequences. In the present study a novel mouse model was characterized to further elucidate the role of astroglial NF-Kappa B signaling in neuroinflammation. This model conditionally expresses a constitutively active mutant of the NF-kappa B activating kinase IKK2 in astrocytes. This results in astroglial NF-kappa B activation, which is sufficient to induce a prominent neuroinflammatory response and impairs brain ...