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

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

DNA methyltransferase 1 (DNMT1) is responsible for copying DNA methylation patterns to the daughter strands during DNA replication. Its expression is frequently up-regulated in human tumors, including hepatocellular carcinoma, but the mechanism of overexpression and its biological significance remain unclear. Here, we show that hepatitis B virus X protein (HBx) activates DNMT1 expression via a regulatory circuit involving the p16(INK4a)-cyclin D1-cyclin-dependent kinase (CDK) 4/6-retinoblastoma protein (pRb)-E2F1 pathway. HBx induced DNA hypermethylation of p16(INK4a) promoter to repress its expression, which subsequently led to activation of G1-CDKs, phosphorylation of pRb, activation of E2F1, and finally transcriptional activation of DNMT1. Inhibition of DNMT1 activity by either treatment with 5'-Aza-2'dC or introduction of DNMT1 small interfering RNA not only abolished the DNA methylation-mediated p16(INK4a) repression but also impaired DNMT1 expression itself, suggesting a cross-talk between DNMT1 and p16(INK4a). The up-regulation of cyclin D1 by HBx is likely to serve as an initiative impulse for the circuit because it was absolutely required for the activation of DNMT1 expression. We also observed that accumulated DNMT1 via this pathway inactivates E-cadherin expression through promoter hypermethylation. Considering that the pRb-E2F1 pathway is commonly activated in human tumors, activation of this circuit might be widespread and a potential therapeutic target.
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PMID:Expression of DNA methyltransferase 1 is activated by hepatitis B virus X protein via a regulatory circuit involving the p16INK4a-cyclin D1-CDK 4/6-pRb-E2F1 pathway. 1757 44

Epithelial cells usually exist as sheets of immotile, tightly packed, well-coupled, polarized cells with distinct apical, basal and lateral surfaces. Remarkably, these cells can dramatically alter their morphology to become motile, fibroblast-like mesenchymal cells in a process of epithelial-mesenchymal transition (EMT). This process and the reverse, mesenchymal-epithelial transition, occur repeatedly during normal embryonic development. A phenomenon similar to physiological EMT occurs during the pathophysiological progression of some cancers. Tumours of epithelial origin, as they transform to malignancy, appear to exploit the innate plasticity of epithelial cells, with EMT conferring increased invasiveness and metastatic potential. Key to the maintenance of epithelial cell identity is the expression of E-cadherin, a protein that is required for tight intercellular adhesion along the lateral surfaces of adjacent epithelial cells. Loss of functional E-cadherin is a critical event in EMT. An important regulator of E-cadherin expression is the protein Snail, a zinc-finger transcriptional repressor. Snail contains several consensus sites for the kinase, glycogen synthase kinase-3 (GSK-3), and accumulating evidence indicates that it is a GSK-3 substrate. Phosphorylation of Snail by GSK-3 facilitates its proteasomal degradation. Conversely, inhibition of GSK-3 leads to Snail accumulation, E-cadherin downregulation, and development of EMT in cultured epithelial cells. Several signalling pathways implicated in the progression of EMT, including the Wnt and phosphoinositide 3-kinase pathways, use GSK-3 to mediate their responses. In these pathways, GSK-3's regulation of other transcriptional effectors like beta-catenin works in concert with changes in Snail to orchestrate the EMT process. This review focuses on the emerging role of GSK-3 as a modulator of cell fate and EMT in the contexts of development, in vitro cell culture and cancer.
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PMID:Role of glycogen synthase kinase-3 in cell fate and epithelial-mesenchymal transitions. 1758 11

PINCH-1 is an adaptor protein that binds to the integrin-linked kinase (ILK), an intracellular serine/threonine protein kinase that plays a critical role in mediating tubular epithelial-to-mesenchymal transition (EMT). To determine whether PINCH-1 is also involved in the EMT process, we investigated its regulation and function during TGF-beta1-stimulated EMT. TGF-beta1 induced PINCH-1 mRNA and protein expression in human proximal tubular epithelial cells in a time-dependent fashion, an effect that was largely dependent on intracellular Smad signaling. Overexpression of PINCH-1 suppressed epithelial markers E-cadherin and ZO-1 and increased fibronectin expression and extracellular assembly, whereas knockdown of PINCH-1 via small interfering RNA reduced TGF-beta1-mediated fibronectin expression and partially restored E-cadherin. PINCH-1 formed a ternary complex with ILK at the focal adhesion sites of tubular epithelial cells. Treatment with an ILK inhibitor or disruption of the ILK/PINCH-1 interaction by overexpressing a dominant-negative N-terminal ankyrin domain of ILK resulted in reduced fibronectin deposition, indicating that the ability of PINCH-1 to stimulate EMT is ILK-dependent. In a mouse model of obstructive nephropathy, PINCH-1 expression increased in a time-dependent manner, suggesting that it may play a role in EMT and renal fibrosis in vivo. We conclude that PINCH-1, through its interaction with ILK, plays an important role in regulating TGF-beta1-mediated EMT and could be a potential future therapeutic target to prevent progression of renal disease.
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PMID:PINCH-1 promotes tubular epithelial-to-mesenchymal transition by interacting with integrin-linked kinase. 1765 71

Esophageal squamous cell carcinoma is frequently associated with poor prognosis, as a result of high levels of lymph node metastasis. So far, very few genetic abnormalities have been associated with this disease, and its molecular etiology remains largely unknown. To assess whether the Wnt pathway contributes to esophageal squamous cell carcinoma, we characterized the expression and subcellular localization of the key Wnt signaling components in all 30 cases of esophageal squamous cell carcinomas analyzed. We found abnormal expression and/or localization in glycogen synthase kinase-3 alpha/beta (34%), Axin2 (48%), alpha-catenin (31%), MYC (73%) and cyclin D1 in 46% of cases. Only 13% of tumors showed nuclear accumulation of beta-catenin. By contrast, 60% showed nuclear expression of E-cadherin using an antibody that recognizes the cytoplasmic domain of E-cadherin. When the same tumors were stained with antibody raised against the extracellular domain of E-cadherin, the expression was lost. A direct correlation was found between nuclear E-cadherin and the increased nuclear cyclin D1, one of the AP-1 target genes in these tumors. By transfection experiments, the cytoplasmic portion of E-cadherin was found to activate the AP-1 transcription factor pathway and induced cyclin D1 promoter activity, but beta-catenin/Tcf transcription activity was unaffected. Nuclear expression of E-cadherin was also detected in tumors other than squamous cell carcinoma, including pancreatic and colon cancers, albeit at lower frequency. Nuclear accumulation of a portion of E-cadherin in esophageal squamous cell carcinoma and the other types of tumors indicates that, in addition to the previously implicated tumor suppressor activity of E-cadherin, modified forms of this glycoprotein might also play a role in growth promotion.
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PMID:Frequent accumulation of nuclear E-cadherin and alterations in the Wnt signaling pathway in esophageal squamous cell carcinomas. 1808 53

Exposure to and bioaccumulation of lipophilic environmental pollutants, such as polycyclic aromatic hydrocarbons (PAHs), has been implicated in breast cancer. Treatment of female rats with the prototypic xenobiotic PAH 7,12-dimethylbenz(a)anthracene (DMBA) induces mammary tumors with an invasive phenotype. Here, we show that green tea prevents or reverses loss of the epithelial marker E-cadherin on the surface of DMBA-induced in situ cancers. To investigate the mechanism(s) leading to a less invasive phenotype, the effects of the green tea polyphenol epigallocatechin-3 gallate (EGCG) on mammary tumor cells were assessed. EGCG reversed epithelial to mesenchymal transition (EMT) in DMBA-treated NF-kappaB c-Rel-driven mammary tumor cells and reduced levels of c-Rel and the protein kinase CK2. Ectopic coexpression of c-Rel and CK2alpha in untransformed mammary epithelial cells was sufficient to induce a mesenchymal gene profile. Mammary tumors and cell lines derived from MMTV-c-Rel x CK2alpha bitransgenic mice displayed a highly invasive phenotype. Coexpression of c-Rel and CK2, or DMBA exposure induced the aryl hydrocarbon receptor (AhR) and putative target gene product Slug, an EMT master regulator, which could be reversed by EGCG treatment. Thus, activation of c-Rel and CK2 and downstream targets AhR and Slug by DMBA induces EMT; EGCG can inhibit this signaling.
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PMID:Green tea polyphenols reverse cooperation between c-Rel and CK2 that induces the aryl hydrocarbon receptor, slug, and an invasive phenotype. 1808 4

Overexpression of zinc finger E-box binding homeobox transcription factor 1 (Zeb1) in cancer leads to epithelial-to-mesenchymal transition (EMT) and increased metastasis. As opposed to overexpression, we show that mutation of Zeb1 in mice causes a mesenchymal-epithelial transition in gene expression characterized by ectopic expression of epithelial genes such as E-cadherin and loss of expression of mesenchymal genes such as vimentin. In contrast to rapid proliferation in cancer cells where Zeb1 is overexpressed, this mesenchymal-epithelial transition in mutant mice is associated with diminished proliferation of progenitor cells at sites of developmental defects, including the forming palate, skeleton and CNS. Zeb1 dosage-dependent deregulation of epithelial and mesenchymal genes extends to mouse embryonic fibroblasts (MEFs), and mutant MEFs also display diminished replicative capacity in culture, leading to premature senescence. Replicative senescence in MEFs is classically triggered by products of the Ink4a (Cdkn2a) gene. However, this Ink4a pathway is not activated during senescence of Zeb1 mutant MEFs. Instead, there is ectopic expression of two other cell cycle inhibitory cyclin-dependent kinase inhibitors, p15Ink4b (Cdkn2b) and p21Cdkn1a (Cdkn1a). We demonstrate that this ectopic expression of p15Ink4b extends in vivo to sites of diminished progenitor cell proliferation and developmental defects in Zeb1-null mice.
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PMID:Zeb1 links epithelial-mesenchymal transition and cellular senescence. 1819 84

E-cadherin, which has a widely acknowledged role in mediating calcium-dependent cell-cell adhesion between epithelial cells, also functions as a tumor suppressor. The ectodomain of human E-cadherin contains four potential N-glycosylation sites at Asn residues 554, 566, 618, and 633. We investigated the role of E-cadherin N-glycosylation in cell cycle progression by site-directed mutagenesis. We showed previously that all four potential N-glycosylation sites of E-cadherin were N-glycosylated in human breast carcinoma MDA-MB-435 cells. Removal of N-glycan at Asn633 dramatically affected E-cadherin stability. In this study we showed that E-cadherin mutant missing N-glycans at Asn554, Asn566 and Asn618 failed to induce cell cycle arrest in G1 phase and to suppress cell proliferation in comparison with wild-type E-cadherin. Moreover, N-glycans at Asn554 and Asn566, but not at Asn618, seemed to be indispensable for E-cadherin-mediated suppression of cell cycle progression. Removal of N-glycans at either Asn554 or Asn566 of E-cadherin was accompanied with the activation of the extracellular signal-regulated protein kinase signaling pathway. After treatment with PD98059, an inhibitor of the extracellular signal-regulated protein kinase signaling pathway, wild-type E-cadherin transfected MDA-MB-435 and E-cadherin N-glycosylation-deficient mutant transfected MDA-MB-435 cells had equivalent numbers of cells in G1 phase. These findings implied that N-glycosylation might be crucial for E-cadherin-mediated suppression of cell cycle progression.
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PMID:N-glycosylation at Asn residues 554 and 566 of E-cadherin affects cell cycle progression through extracellular signal-regulated protein kinase signaling pathway. 1823 76

Feeder-free culture induces spontaneous differentiation of human embryonic stem cells (hESCs), identified as an epithelial to mesenchymal transition (EMT). The maintenance of pluripotency of hESCs in feeder-free cultures through the activation of the WNT pathway using a glycogen synthase kinase (GSK)-3-specific inhibitor (BIO) was reported. The aim of this study was to determine the effect of BIO on the EMT process. In contrast with those grown in feeder-free conditions with control medium, hESC colonies cultured with BIO-supplemented hESC medium did not show any fibroblast-like cells at the periphery. Transmission electron microscopy, relative quantitative real-time RT-PCR and immunostaining analyses showed the presence of epithelial features and a diminution of mesenchymal features in the BIO-treated hESCs such as a strong E-cadherin expression, the down-regulation of Vimentin, Snail and Slug expressions and a cytoplasmic beta-catenin expression. An up-regulation of matrix metalloproteinases (MMP) MMP-2, MMP-9, MT-1MMP (membrane-type 1 MMP) and EMMPRIN (extracellular MMP inducer) expression was also found associated with the EMT occurring in feeder-free hESCs cultures using mouse embryonic fibroblasts conditioned medium (MEF CM). The presence of BIO clearly down-regulated the expression of these MMPs. This study showed that BIO, a GSK-3-specific inhibitor, prevents the EMT process which is associated with the feeder-free hESC culture. Nevertheless, BIO was not sufficient to expand hESCs in a long-term culture system.
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PMID:GSK-3-specific inhibitor-supplemented hESC medium prevents the epithelial-mesenchymal transition process and the up-regulation of matrix metalloproteinases in hESCs cultured in feeder-free conditions. 1826 7

To investigate the pathobiological behaviors of gastric mixed-type (MT) carcinomas and gastric carcinogenesis, the clinicopathological characteristics of MT carcinomas were analyzed and compared with intestinal-type (IT) and diffuse-type (DT) carcinomas. The expression of Ki-67, caspase-3, p53, fragile histine triad (FHIT), maspin, extracellular matrix metalloproteinase inducer (EMMPRIN), vascular growth factor (VEGF), MUC-2, 4, 5AC and 6, CD44, E-cadherin, beta-catenin, and phosphorylated glycogen synthase kinase 3beta-ser9 (P-GSK3beta-ser9) was examined on tissue microarrays using immunohistochemistry. It was found that MT carcinomas exhibited large size, deep invasion, frequent local invasion, and lymph node metastasis in comparison with IT and DT carcinomas (p < 0.05). All the markers except MUC-5AC showed higher expression in IT than DT carcinomas (p < 0.05). The expression of maspin, EMMPRIN, VEGF, MUC-4, and membrane E-cadherin was stronger in MT intestinal than diffuse component (p < 0.05). Immunoreactivities to Ki-67, EMMPRIN, and VEGF were weaker in IT carcinoma than in the MT intestinal portion (p < 0.05), while the opposite was true for CD44, MUC-2, and MUC-6 (p < 0.05). The MT diffuse component displayed a higher expression of FHIT, VEGF, and P-GSK3beta-ser9 than DT carcinoma (p < 0.05). The accumulative survival rate of the IT carcinoma patients was higher than the other types (p < 0.05). The invasive depth, venous invasion, lymph node, peritoneal or liver metastasis, and Lauren's classification were independent prognostic factors for gastric carcinomas (p < 0.05). These findings suggested that MT carcinomas were also indicated to be more aggressive than IT and DT carcinomas. Significant differences were observed in the proliferation, apoptosis, angiogenesis, mucin secretion, and cell adhesion between IT and DT carcinomas, whereas only a few of these characteristics showed differences between the MT intestinal and diffuse parts, thus suggesting that both the MT components might originate from the stem cells with similar genetic traits, but follow different histogenic pathways.
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PMID:Mixed-type gastric carcinomas exhibit more aggressive features and indicate the histogenesis of carcinomas. 1826 6

Dysregulation of protein kinase A (PKA) activity, caused by loss of function mutations in PRKAR1A, is known to induce tumor formation in the inherited tumor syndrome Carney complex (CNC) and is also associated with sporadic tumors of the thyroid and adrenal. We have previously shown that Prkar1a(+/-) mice develop schwannomas reminiscent of those seen in CNC and that similar tumors are observed in tissue-specific knockouts (KO) of Prkar1a targeted to the neural crest. Within these tumors, we have previously described the presence of epithelial islands, although the nature of these structures was unclear. In this article, we report that these epithelial structures are derived from KO cells originating in the neural crest. Analysis of the mesenchymal marker vimentin revealed that this protein was markedly down-regulated not only from the epithelial islands, but also from the tumor as a whole, consistent with mesenchymal-to-epithelial transition (MET). In vitro, Prkar1a null primary mouse embryonic fibroblasts, which display constitutive PKA signaling, also showed evidence for MET, with a loss of vimentin and up-regulation of the epithelial marker E-cadherin. Reduction of vimentin protein occurred at the posttranslational level and was rescued by proteasomal inhibition. Finally, this down-regulation of vimentin was recapitulated in the adrenal nodules of CNC patients, confirming an unexpected and previously unrecognized role for PKA in MET.
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PMID:Targeted deletion of Prkar1a reveals a role for protein kinase A in mesenchymal-to-epithelial transition. 1841 34


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