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Subsequently, we pioneered the identification of arginine 30 R30 methylation of p65 [ 22 ]. To date, a total of six lysine methylation sites have been reported: K37, , , , , and [ 18 , 20 ]. By using a novel genetic approach, our lab identified that p65 can be methylated by a lysine methylase, the nuclear receptor-binding SET domain-containing protein 1 NSD1 , and demethylated by a lysine demethylase, the F-box and leucine-rich repeat protein 11 FBXL11 [ 20 ].

Zhang et al.


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The methylation of p65 blocks recruitment of PP2A to p65, thereby leading to the persistent phosphorylation of p65 [ 34 ]. By using the immunohistochemistry IHC staining method, the authors showed that PHF20 and phosphorylated p65 are localized in the nucleus in glioma tissue specimens.

The PHF20 expression levels are also tightly correlated with the clinical tumor grade after univariate analysis with a P value of 0. Methylated p65 stays in the nucleus, and Set9 might regulate its nuclear function. Interestingly, Yang et al. Collectively, this evidence suggests the complexity of p65 methylation, and indicates that the same enzyme, such as SET9, may have different functions depending on the lysine residues it modifies. Besides the methylated lysine residues on p65 discussed above, another SET family member SETD6, was also reported to monomethylate p65 at K under basal condition.

Levy and colleagues observed that under the unstimulated condition, a proportion of p65 can be monomethylated by SETD6. The phenotype was proven in various cell lines, such as bone osteosarcoma U2OS, peripheral blood THP-1, and bone marrow-derived macrophages BMDM , and therefore represents diverse disease models. Interestingly, Levy et al. By binding to monomethylated K, GLP enriches histone H3K9 dimethylation on the p65 target gene promoters, resulting in gene suppression.

Distinct from the methylation of lysine residues, our lab used Mass Spectrometry to discover that p65 can also be symmetrically methylated at arginine 30 residue R30 [ 20 , 22 ]. This important modification is carried out by the protein arginine methyltransferase 5 PRMT5 , an enzyme that belongs to the PRMT superfamily, contains amino acids, and catalyzes the formation of symmetrically dimethylated arginine.

Conditional media from cells expressing the R30A mutant of p65 had much less NF-kB-inducing activity than its wild-type cohort. Additionally, through In Silico prediction we proposed that dimethylation of R30 may mediate van der Waals contacts and stabilize domain interactions. The key residues involved are aspartic acid D , glutamic acid E , and threonine T This evidence affirms the importance of R30 methylation in increasing the ability of p65 to bind to DNA, resulting in the changes in its target gene expression [ 22 ].

Further demonstrating the complexity of R30 methylation, Reintjes et al. Different from PRMT5, PRMT1 is an enzyme containing amino acids which catalyzes the formation of monomethyl-arginine and asymmetric dimethyl-arginine [ 36 ]. Reintjes and colleagues proposed an interesting model suggesting that symmetric dimethylation of R30 by PRMT5 seems to be induced at early time points, however, asymmetric dimethylation of R30 by PRMT1 is enriched at later time points.

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As we mentioned earlier, a total of six lysine methylation sites can be methylated by different histone lysine methyltransferases in response to activating signals. However, their expression is much more stable than the EGR gene [ 21 ]. This is a very interesting phenomenon. Illumina microarray experiments were carried out to analyze the gene populations affected by these mutations. However, these two networks show quite distinct topographies and interactions with other signaling components. Signaling to NF-kappaB. Negative regulation of toll-like receptor signaling by NF-kappaB p50 ubiquitination blockade.

Hypoxia-inducible factor 1 alpha activates and is inhibited by unoccupied estrogen receptor beta. J Biol Chem, 28 Scheidereit C IkappaB kinase complexes: gateways to NF-kappaB activation and transcription. Signaling mechanisms involved in the response to genotoxic stress and regulating lifespan.

Antiproliferative and antiapoptotic effects of crel may occur within the same cells via the up-regulation of manganese superoxide dismutase. Nuclear factor kappaB subunits induce epithelial cell growth arrest. Cell autonomous expression of inflammatory genes in biologically aged fibroblasts associated with elevated NF-kappaB activity. Changes associated with aging and replicative senescence in the regulation of transcription factor nuclear factor-kappa B. Age-related changes in the regulation of transcription factor NF-kappa B in rat brain. The ubiquitin-proteasome system at the crossroads of stress-response and ageing pathways: a handle for skin care?.

Growing old with nuclear factor-kappaB. Cell, 43 Natoli G When sirtuins and NF-kappaB collide. A human-like senescence-associated secretory phenotype is conserved in mouse cells dependent on physiological oxygen.


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    Inflamm Res, 53 Kenyon CJ The genetics of ageing. Insulin antiapoptotic signaling involves insulin activation of the nuclear factor kappaB-dependent survival genes encoding tumor necrosis factor receptor-associated factor 2 and manganese-superoxide dismutase. Insulin like growth factor-1 activates nuclear factor-kappaB and increases transcription of the intercellular adhesion molecule-1 gene in endothelial cells. Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Effects of trans-resveratrol from Polygonum cuspidatum on bone loss using the ovariectomized rat model.

    Resveratrol improves health and survival of mice on a high-calorie diet. Sirtuins--novel therapeutic targets to treat age-associated diseases. Sirt1 interacts with transducin-like enhancer of split-1 to inhibit nuclear factor kappaB-mediated transcription. Aging in Saccharomyces cerevisiae. Annu Rev Microbiol, 72 Guarente L Sir2 links chromatin silencing, metabolism, and aging. Genes Dev, 73 Peng SL Immune regulation by Foxo transcription factors. Regulation of NF-kappaB, Th activation, and autoinflammation by the forkhead transcription factor Foxo3a. The TOR pathway interacts with the insulin signaling pathway to regulate C.

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    Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. NF-kappaB signaling in the aging process. Differential involvement of IkappaB kinases alpha and beta in cytokine- and insulin-induced mammalian target of rapamycin activation determined by Akt. Parallels in genome-wide expression changes between long-lived and progeroid mice reveal a survival response promoting longevity.

    A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis. Signaling transduction: target in osteoarthritis. Role of the NF-kappaB pathway in the pathogenesis of human disease states. Antioxidant alpha-lipoic acid inhibits osteoclast differentiation by reducing nuclear factor-kappaB DNA binding and prevents in vivo bone resorption induced by receptor activator of nuclear factor-kappaB ligand and tumor necrosis factor-alpha.

    Signal transduction through nuclear factor kappa B in ischemia-reperfusion and heart failure.

    Nuclear Factor кB

    Basic Res Cardiol, 92 Steinman L Nuanced roles of cytokines in three major human brain disorders. Brain interleukin 1 and S immunoreactivity are elevated in Down syndrome and Alzheimer disease. High cholesterol diet results in increased expression of interleukin-6 and caspase-1 in the brain of apolipoprotein E knockout and wild type mice. In vivo and in vitro evidence supporting a role for the inflammatory cytokine interleukin-1 as a driving force in Alzheimer pathogenesis.

    Inflammation in Alzheimer disease: driving force, bystander or beneficial response?. Tumor necrosis factor-alpha TNF-alpha increases both in the brain and in the cerebrospinal fluid from parkinsonian patients. Early impairment in dopaminergic neurotransmission in brains of SIV-infected rhesus monkeys due to microglia activation. Microglial inflammation in the parkinsonian substantia nigra: relationship to alpha-synuclein deposition.

    Evidence of active microglia in substantia nigra pars compacta of parkinsonian monkeys 1 year after MPTP exposure. Distinct role for microglia in rotenone-induced degeneration of dopaminergic neurons. Susceptibility to rotenone is increased in neurons from parkin null mice and is reduced by minocycline. Femtomolar concentrations of dextromethorphan protect mesencephalic dopaminergic neurons from inflammatory damage.

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    Nuclear translocation of NF-kappaB is increased in dopaminergic neurons of patients with parkinson disease. Activation of nuclear transcription factor kappa B NF-kappaB is essential for dopamine-induced apoptosis in PC12 cells. Systemic infections and inflammation affect chronic neurodegeneration. Inflammatory process in type 2 diabetes: The role of cytokines. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta.

    Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. CXCL14 deficiency in mice attenuates obesity and inhibits feeding behavior in a novel environment. Adenoviral gene transfer of the interleukin-1 receptor antagonist protein to human islets prevents IL-1beta-induced beta-cell impairment and activation of islet cell apoptosis in vitro. Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function.

    Canonical pathway of nuclear factor kappa B activation selectively regulates proinflammatory and prothrombotic responses in human atherosclerosis. Cytokines and atherosclerosis: a comprehensive review of studies in mice. Vasculoprotective effects of anti-tumor necrosis factor-alpha treatment in aging. Effect of muscle mass decrease on age-related BMR changes. Circulating acute phase mediators and skeletal muscle performance in hospitalized geriatric patients. The protein methyltransferases include two enzymes, the protein lysine methyltransferases and the protein arginine methyltransferases PRMTs.

    Both enzymes use small-molecule cofactor, S -adenosyl-l-methionine, as the universal methyl donor for the enzymatic methylation of lysine and arginine side chains. It has been suggested that the methylation of p65 in the nucleus potentially facilitates binding to specific promoters when the local chromatin remodeling machinery is active. For example, phosphorylation at Ser and Ser enhances the p and PCAF-mediated acetylation of Lys, Lys, and Lys and upregulates transcriptional activation by p The varied and differential outcomes following individual site phosphorylation or acetylation have been attributed to the induced conformational changes in p65 that direct subsequent cofactor interactions required for transcriptional activation.

    Dephosphorylation of Ser by protein phosphatase 2A or by wild-type pinduced phosphatase 1 has been shown to reduce the interaction of p65 with p and thereby inhibit gene expression. Demethylation of p Similar to phosphorylation and acetylation, methylation is also a reversible event mediated by demethylases. Several interrelated not mutually exclusive mechanisms regulate the stability and termination of nuclear p In addition, the nature and extent of regulation by post-translational modification can vary with different stimulators and even the same modifications can facilitate different effects.

    These compounds belong to different chemical classes such as naturetics, peptidomimetics, small molecules, small interfering RNAs, and microbial products Table 1. Table 1 Strategies and agents developed and evaluated for selective targeting of NF-kB p Notes: The table includes representative examples of agents evaluated for selective targeting of p65 in the context of chronic inflammation.

    Notes: The inset shows phosphorylation and acetylation sites of p65 as sites of kinase inhibitors and HDACs. Representative inhibitory strategies along the pathway are shown. Hence, preventing phosphorylation by using kinase inhibitors constitutes attractive therapeutic strategy. A vast number of kinase inhibitors target either the IKK complex or the adapter proteins in the NF-kB signal transduction pathway please refer to excellent reviews 3 , 71 , 73 , The therapeutic potential of these kinase inhibitors has been predominantly evaluated in multiple cancers.

    For example, p38 mitogen-activated protein kinase MAPK inhibitor has been shown to inhibit phosphorylation of the coactivator p and preclude acetylation on Lys of p65, thereby preventing DNA binding and transcriptional activity. NLS inhibitors: As stated above, nucleocytoplasmic shuttling of p65 is critical for transcriptional regulation of target genes. Examples of this class of inhibitors include small molecules such as inhibitor of nuclear import and selinexor, a selective inhibitor of nuclear export compound that inhibits the exportin XPO1.

    Blocking p65 TAD: This includes strategies that inhibit p65 independent of other rel proteins. Competing p65 peptide: The p65 nuclear translocation and consequent transactivation of target genes is facilitated by interactions of pTAD with other transcription factors and cofactors. A conceptually simple strategy for development of inhibitors of interprotein interactions is to take advantage of the evolutionary selection of residues for individual protein:protein interaction and design interface peptides derived from the primary sequence of one of the binding partners.

    Glucocorticoids-mediated cytoplasmic sequestration of p The classical model for the therapeutic potential of glucocorticoids suggests that the direct binding of the glucocorticoid receptor on specific glucocorticoid receptor elements GREs in the promoter region upregulates transactivation of anti-inflammatory genes. Among the proteins that bind p65, a subset directly binds the TAD such as the p, 95 , 96 silencing mediator of retinoic acid and thyroid hormone receptors 97 and the Smad proteins.

    In humans, eight Smads are known and are classified into three subtypes: five receptor-regulated Smads R-Smads , one common partner Smad co-Smad , and two inhibitory Smads I-Smad. Structurally, the Smad proteins have two conserved globular domains called the mad homology MH 1 and MH2 domains. Decoy oligodeoxynucleotides decoy ODNs : They constitute a type of gene therapy and are made up of double-stranded DNA fragments of the same sequence as the binding site of the transcription factor on DNA.

    However, limited cellular uptake due to the negative charge and large size as well as severe toxicities due to lack of cellular restrictions is a potential drawback. Recently, several strategies have been developed for successful and targeted delivery of decoy ODNs such as the use of nanoparticles and ultrasound-targeted microbubbles. The dynamic nature of the PTMs in regulating gene expression patterns makes this system particularly amenable for epigenetic drug discovery. Although all PTMs are important components of the epigenome, acetylation network consists of a large number of druggable targets.

    The following include few examples of HAT inhibitors that selectively target lysine residues on p PCAF inhibitors: The PCAF inhibitors specifically acetylate only Lys of p65 and blocking of this acetylation could diminish the nuclear retention and transcriptional activity of p Tip60, a member of the MYST family of co-activators, has been shown to activate pmediated transcription by maintaining the Lys in the acetylated state.

    The arginine methyltransferase, PRMT5, that demethylates R30 of p65 plays a key role in regulating endothelial cell inflammation, proliferation, and differentiation. As discussed earlier, several strategies to block p65 at each level along the path of signaling have been assessed and novel strategies are being developed. However, a critical hurdle is selective targeting of activated p65 without the off-target effects. In this context, steric blockade of pTAD using GILZ mimetics or mimics of the pSmad4 interface appears to be a promising strategy to selectively inhibit activated p It is anticipated that advances in nanotechnology-based delivery systems will assist in not only improving the pharmacokinetic profile but also facilitate contextual delivery of drugs and drug-like agents.

    Recently, a nanocarrier delivery system consisting of a functional cell-penetrating stearoyl-oligopeptide was used for effective delivery of two RNAi agents that silenced p65 mRNA in macrophages and exerted therapeutic effects in a model of atopic dermatitis. In future, development of engineered nanocarriers will not only facilitate targeted delivery but also accommodate conformational changes needed for efficacious intracellular p65 inhibitors.

    Immunol Rev.

    Research Journals

    Oeckinghaus A, Ghosh S. The NF-kappaB family of transcription factors and its regulation. Cold Spring Harb Perspect Biol. Nat Rev Drug Discov. Sci Signal. Nat Immunol. Cell Res. Nat Rev Mol Cell Biol. The molecular mechanism of transport of macromolecules through nuclear pore complexes.

    Biol Direct. J Biol Chem. The p65 subunit is responsible for the strong transcription activating potential of NF-kappa B. Embo J. Two modes of transcriptional activation at native promoters by NF-kappaB p PLoS Biol. Centrosomal P4.

    see

    NF-κB: a key role in inflammatory diseases

    Involvement of the pro-oncoprotein TLS translocated in liposarcoma in nuclear factor-kappa B pmediated transcription as a coactivator. Proc Natl Acad Sci. Mol Cell Biol. Baldwin AS. BMC Syst Biol. Evidence for distinct substrate specificities of importin alpha family members in nuclear protein import. Cell Signal. Barnes PJ. Kinases as novel therapeutic targets in asthma and chronic obstructive pulmonary disease. Pharmacol Rev. PLoS One. Mol Cell.

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    The role of RelA p65 threonine phosphorylation in the regulation of cell growth, survival, and migration. Mol Biol Cell. Karin M, Ben-Neriah Y. Annu Rev Immunol. IkappaB kinases phosphorylate NF-kappaB p65 subunit on serine in the transactivation domain. Trends Biochem Sci. Small molecule inhibitors of histone acetyltransferases and deacetylases are potential drugs for inflammatory diseases.