Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:2.7.11.10 (IKK)
4,900 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Post-translational modification of the p53 family members is key to their regulation. Here we report the phosphorylation of TAp63gamma, but not DeltaNp63gamma, by IkappaB kinase beta (IKKbeta). Activation of IKKbeta by gamma radiation or tumor necrosis factor-alpha led to increased TAp63gamma protein levels in cells. IKKbeta, but not its kinase-defective mutant IKKbeta-K44A, led to this observed stabilization of TAp63gamma. This stabilization of TAp63gamma in response to gamma radiation was significantly decreased in the absence of IKKbeta. Phosphorylation of TAp63gamma blocks ubiquitylation and possible degradation of this protein. We postulate that phosphorylation of TAp63gamma by IKKbeta stabilizes the TAp63gamma protein by blocking ubiquitylation-dependent degradation of this protein.
...
PMID:Phosphorylation and stabilization of TAp63gamma by IkappaB kinase-beta. 1841 Dec 64

Elongator, a multi-subunit complex assembled by the IkappaB kinase-associated protein (IKAP)/hELP1 scaffold protein is involved in transcriptional elongation in the nucleus as well as in tRNA modifications in the cytoplasm. However, the biological processes regulated by Elongator in human cells only start to be elucidated. Here we demonstrate that IKAP/hELP1 depleted colon cancer-derived cells show enhanced basal expression of some but not all pro-apoptotic p53-dependent genes such as BAX. Moreover, Elongator deficiency causes increased basal and daunomycin-induced expression of the pro-survival serum- and glucocorticoid-induced protein kinase (SGK) gene through a p53-dependent pathway. Thus, our data collectively demonstrate that Elongator deficiency triggers the activation of p53-dependent genes harbouring opposite functions with respect to apoptosis.
...
PMID:Deregulated expression of pro-survival and pro-apoptotic p53-dependent genes upon Elongator deficiency in colon cancer cells. 1843 Apr 10

Genomic instability during hepatocarcinogenesis causes changes in signal transduction network. Strategies for identification of new markers/therapeutic targets include discovery of early molecular changes during hepatocarcinogenesis, relevant to preneoplastic lesions progression to full malignancy in rodent models, and evaluation of these changes in human hepatocellular carcinomas (HCCs). Activation of ERB receptor family, MAPK, JAK-STAT, beta-Catenin cascades, c-Myc targets, iNOS-IKK/MAT1A-NF-kB axis, Ornithine decarboxylase, Cyclins and CDKs occurs in human and rodent hepatocarcinogenesis. This is associated with downregulation of the cell cycle inhibitors p16(INK4A) and p53 and TGF-beta/SMAD signaling. Oncosuppressor genes, including p16(INK4A), E-CAD, and DLC-1 are often hypermethylated in humans and rodents. Moreover, protection of cell cycle from p16(INK4A) inhibition by upregulation of CDC37, HSP90, and CRM1 correlates to HCC progression. A body of evidence indicates that inhibition of key genes of aforementioned signaling pathways by antisense or siRNA approaches or specific inhibitors restraints growth of in vitro cultured or in vivo xenografted HCCs. Efforts are currently dedicated to improve transduction efficiency. HCC cells may escape gene therapy by various mechanisms. Attempts to overcome this difficulty include discovery of new therapeutic targets, gene therapy directed to different molecular targets essential for tumor cell survival and specifically directed to HCC subtypes.
...
PMID:Dissection of signal transduction pathways as a tool for the development of targeted therapies of hepatocellular carcinoma. 1847 8

NF-kappaB plays an important role in oncogenesis. Recently, we have demonstrated that loss of p53 function enhances DNA binding and transcriptional activities of NF-kappaB via IKKalpha and IKKbeta, and that glycolysis, activated by NF-kappaB, has an integral role in oncogene-induced cell transformation. Here, we show that ectopically expressed p53 induces acetylation and phosphorylation at Ser 536 of p65, an NF-kappaB component, and enhances DNA-binding activity of NF-kappaB. However, activated p53 suppresses transcriptional activity of NF-kappaB. Under non-stimulating conditions, p65 formed a complex with IKKalpha and IKKbeta. Activated p53 bound to p65 on DNA and disrupted binding of p65 to IKKbeta. Moreover, histone H3 kinase activity, which requires transcriptional activation of NF-kappaB, was diminished by p53. Thus, activated p53 may suppress transcriptional activity of NF-kappaB through inhibition of IKK and histone H3 kinase on DNA, suggesting a novel p53-mediated suppression system for tumorigenesis.
...
PMID:Activated p53 induces NF-kappaB DNA binding but suppresses its transcriptional activation. 1847 70

Functional inactivation of p53 and constitutive activation of the NF-kappaB pathway has been associated with several human cancers. In this study, we show that IkappaB kinase 2 (IKK2/IKKbeta), which is critical for NF-kappaB activation, also phosphorylates p53. Phosphorylation of p53 at serines 362 and 366 by IKK2 leads to its recruitment to and ubiquitination by beta-TrCP1. Degradation of ubiquitinated p53 is independent of Mdm2, because it occurs in both wild-type and Mdm2(-/-) cells. SiRNA-mediated reduction in the levels of beta-TrCP1 and other members of the SCF(beta-TrCP1)E3 ubiquitin ligase complex or overexpression of a dominant negative form of beta-TrCP1 enhances p53 stability. Substitutions at Ser-362 and 366 of p53 by alanines (p53 AA) result in reduced phosphorylation of p53 by IKK2, decreased association with beta-TrCP1, and thus increased stability of p53 and expression of p53 target genes such as p21, altering the G1 phase of the cell cycle. Our results identify IKK2 and beta-TrCP1 as novel regulators of the p53 pathway and suggest that blocking of IKK2 and beta-TrCP1 could be a means of regulating p53 stability and thereby modulating its biological activity.
...
PMID:Phosphorylation of p53 by IkappaB kinase 2 promotes its degradation by beta-TrCP. 1919 87

The IkappaB kinase (IKK)-NF-kappaB pathway plays a critical role in oncogenesis. Recently, we have shown that p53 regulates glucose metabolism through the IKK-NF-kappaB pathway and that, in the absence of p53, the positive feedback loop between IKK-NF-kappaB and glycolysis has an integral role in oncogene-induced cell transformation. Here, we demonstrate that IKKbeta, a component of the IKK complex, was constitutively modified with O-linked beta-N-acetyl glucosamine (O-GlcNAc) in both p53-deficient mouse embryonic fibroblasts (MEFs) and transformed human fibroblasts. In p53-deficient cells, the O-GlcNAcylated IKKbeta and the activating phosphorylation of IKK were decreased by p65/NF-kappaB knockdown or glucose depletion. We also found that high glucose induced the O-GlcNAcylation of IKKbeta and sustained the TNFalpha-dependent IKKbeta activity. Moreover, the O-GlcNAcase inhibitor streptozotocin intensified O-GlcNAcylation and concomitant activating phosphorylation of IKKbeta. Mutational analysis revealed that O-GlcNAcylation of IKKbeta occurred at Ser 733 in the C-terminal domain, which was identified as an inactivating phosphorylation site, suggesting that IKKbeta O-GlcNAcylation regulates its catalytic activity. Taken together, we propose a novel mechanism for the enhancement of NF-kappaB activity by loss of p53, which evokes positive feedback regulation from enhanced glucose metabolism to IKK in oncogenesis.
...
PMID:Loss of p53 enhances catalytic activity of IKKbeta through O-linked beta-N-acetyl glucosamine modification. 1920 66

Elevated levels of NF-kappaB are frequently detected in many inflammatory diseases and cancers. Blocking the IKK-NF-kappaB pathway has been seen as a promising approach for new therapies. By employing the dominant-negative mutant of IKKbeta, our data revealed that loss of IKKbeta activity reduces not only the proliferation and invasion of lung adenocarcinoma A549 cells in vitro but also the tumour formation, metastasis and angiogenesis in mouse xenograft model. Treatment of IKKbeta inhibitors (CYL-19s and CYL-26z) leads to the arrest of cell cycle progression at G1 and G2/M, followed by apoptosis. IKKbeta inhibitors can increase the protein stability, nuclear accumulation and promoter-binding activity of p53, leading to the p21 gene transcription. Furthermore, knockdown of IKKbeta by siRNA increased the stability and expression of p53 and p21 promoter activity. In addition, IKKbeta inhibitor-induced p53 and p21 expressions were augmented in the presence of IKKbeta siRNA. Correlation between p53 acetylation and its protein stabilization was also seen after treatment with IKKbeta inhibitors. These results suggest that loss of IKKbeta activation is important for the enhancement of p53 stability, leading to p21 expression and cell cycle arrest and apoptosis of tumour cells.
...
PMID:Loss of IKKbeta activity increases p53 stability and p21 expression leading to cell cycle arrest and apoptosis. 1924 72

The BRAFV600E mutation is common in human melanoma. This mutation enhances IkappaB kinase (IKK)/nuclear factor-kappaB (NF-kappaB) and extracellular signal-regulated kinase/activator protein signaling cascades. In this study, we evaluated the efficacy of targeting either B-Raf or IKKbeta in combination with the DNA alkylating agent temozolomide for treatment of advanced metastatic melanoma. Xenografts of Hs294T human metastatic melanoma cells exhibiting the BRAFV600E mutation were treated with inhibitors of IKKbeta (BMS-345541), B-Raf (BAY 54-9085), and/or temozolomide. Drug response was mechanistically analyzed in vitro and in vivo. In this study, we determined that the antitumor activity of all three drugs depends on inhibition of NF-kappaB. BMS-345541 inhibits IKKbeta-mediated phosphorylation of IkappaBalpha and thus blocks the nuclear localization of NF-kappaB, whereas BAY 54-9085 inhibits activation of NF-kappaB through a mechanism that does not involve stabilization of IkappaBalpha. Moreover, BMS-345541, but not BAY 54-9085, activates the death pathways of p53 and c-Jun-NH2-kinase, contributing to the killing of melanoma cells. Temozolomide inhibits both NF-kappaB and extracellular signal-regulated kinase activity, conferring effective in vivo antitumor activity. Thus, temozolomide, but not BAY 54-9085, has a synergistic in vivo antitumor effect with BMS-345541. We conclude that the efficacy of antimelanoma therapy depends on inhibition of expression of antiapoptotic genes transcriptionally regulated by NF-kappaB. In contrast, drug targeting of the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway alone in melanoma cells is ineffective for melanoma therapy in cases where NF-kappaB is not also targeted.
...
PMID:Molecular determinants of melanoma malignancy: selecting targets for improved efficacy of chemotherapy. 1927 65

During carcinogenesis, NF-gammaB mediates processes associated with deregulation of the normal control of proliferation, angiogenesis, and metastasis. Thus, suppression of NF-gammaB has been linked with chemoprevention of cancer. Accumulating findings reveal that heat shock protein 90 (HSP90) is a molecular chaperone and a component of the IgammaB kinase (IKK) complex that plays a central role in NF-gammaB activation. HSP90 also stabilizes key proteins involved in cell cycle control and apoptosis signaling. We have determined whether the exogenous administration of isoflavone-deprived soy peptide prevents 7,12-dimethylbenz[alpha]anthracene (DMBA)-induced rat mammary tumorigenesis and investigated the mechanism of action. Dietary administration of soy peptide (3.3 g/rat/day) significantly reduced the incidence of ductal carcinomas (50%), the number of tumors per multiple tumor-bearing rats (49%; P<0.05), and extended the latency period of tumor development (8.07+/-0.92 weeks) compared to control diet animals (10.80+/-1.30; P<0.05). Our results have further demonstrated that soy peptide (1) dramatically inhibits the expression of HSP90, thereby suppressing signaling pathway leading to NF-gammaB activation; (2) induces expression of p21, p53, and caspase-3 proteins; and (3) inhibits expression of VEGF. In agreement with our in vivo data, soy peptide treatment inhibited the growth of human breast MCF-7 tumor cells in a dose-dependent manner and induced apoptosis. Taken together, our in vivo and in vitro results suggest chemopreventive and tumor suppressive functions of isoflavone-deprived soy peptide by inducing growth arrest and apoptosis.
...
PMID:Isoflavone-deprived soy peptide suppresses mammary tumorigenesis by inducing apoptosis. 1932 27

Inflammatory changes are a major component of the normal tissue response to ionizing radiation, and increased nuclear factor kappaB (NF-kappaB) activity is an important mediator of inflammatory responses. Here, we used zebrafish embryos to assess the capacity of two different classes of pharmacologic agents known to target NF-kappaB to modify radiation toxicity in the vertebrate organism. These were proteasome inhibitors, including lactacystin, MG132, and PS-341 (Bortezomib/VELCADE), and direct inhibitors of NF-kappaB activity, including ethyl pyruvate (EP) and the synthetic triterpenoid CDDO-TFEA (RTA401), among others. The proteasome inhibitors either did not significantly affect radiation sensitivity of zebrafish embryos (MG132, lactacystin) or rendered zebrafish embryos more sensitive to the lethal effects of ionizing radiation (PS-341). Radiosensitization by PS-341 was reduced in fish with impaired p53 expression or function but not associated with enhanced expression of select p53 target genes. In contrast, the direct NF-kappaB inhibitors EP and CDDO-TFEA significantly improved overall survival of lethally irradiated zebrafish embryos. In addition, direct NF-kappaB inhibition reduced radiation-induced apoptosis in the central nervous system, abrogated aberrations in body axis development, restored metabolization and secretion of a reporter lipid through the gastrointestinal system, and improved renal clearance compromised by radiation. In contrast to amifostine, EP and CDDO-TFEA not only protected against but also mitigated radiation toxicity when given 1 to 2 hours postexposure. Finally, four additional IkappaB kinase inhibitors with distinct mechanisms of action similarly improved overall survival of lethally irradiated zebrafish embryos. In conclusion, inhibitors of canonical pathways to NF-kappaB activation may be useful in alleviating radiation toxicity in patients.
...
PMID:Nuclear factor kappaB inhibitors alleviate and the proteasome inhibitor PS-341 exacerbates radiation toxicity in zebrafish embryos. 1972 85


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---