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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Enterotoxins of Staphylococcus aureus are among the most common causes of food poisoning. Acting as superantigens they intoxicate the organism by causing a massive uncontrolled T cell activation that ultimately may lead to toxic shock and death. In contrast to our detailed knowledge regarding their interaction with the immune system, little is known about how they penetrate the epithelial barrier to gain access to their targets. We therefore studied the uptake of two staphylococcal enterotoxins (SEs), SEA and SEB, using organ cultured porcine jejunal explants as model system. Attachment of both toxins to the villus surface was scarce and patchy compared with that of cholera toxin B (CTB). SEA and SEB also bound to microvillus membrane vesicles in vitro, but less efficiently than CTB, and the binding was sensitive to treatment with endoglycoceramidase II, indicating that a glycolipid, possibly digalactosylceramide, acts as cell surface receptor at the brush border. Both SEs partitioned poorly with detergent resistant membranes (DRMs) of the microvillus, suggesting a weak association with lipid raft microdomains. Where attachment occurred, cellular uptake of SEA and SEB was also observed. In enterocytes, constitutive apical endocytosis normally proceeds only to subapical early endosomes present in the actomyosin-rich "terminal web" region. But, like CTB, both SEA and SEB penetrated deep into the cytoplasm. In conclusion, the data show that after binding to the enterocyte brush border SEA and SEB perturb the apical membrane trafficking, enabling them to engage in transcytosis to reach their target cells in the subepithelial lamina propria.
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PMID:Staphylococcus aureus enterotoxins A- and B: binding to the enterocyte brush border and uptake by perturbation of the apical endocytic membrane traffic. 2318 Mar 9

The main limitation of using topical corticosteroids in dermatology is their atrophic effects on the skin. We have previously proposed a molecular platform composed of CD44, EGFR, and hyaluronate synthase (HAS) that is functionally defective in dermatoporosis, a chronic cutaneous insufficiency/fragility syndrome. In this study, we explored the molecular mechanisms of the skin atrophy induced by corticosteroids. We observed an important skin atrophy and a significant decrease of hyaluronic acid (HA), its main cell surface receptor CD44, and F-actin in mouse skin treated with topical clobetasol propionate (CP). Human keratinocytes exposed to CP showed an impaired HA secretion and diminished expression of CD44 and HAS3. CP also abolished filopodia of keratinocytes exposed to CP together with a redistribution of CD44 and F-actin depolymerization. We also show that HA fragments of intermediary size (HAFi) induced keratinocyte filopodia and protected them against CP. Topical HAFi induced hyperplasia in mouse epidermis and prevented CP-induced atrophy. Our results suggest that a CD44/EGFR/HAS platform associated with F-actin and filopodia of keratinocytes is the target of corticosteroids for their atrophogenic effects. These observations may lead to the development of new treatment and prevention strategies for corticosteroid-induced skin atrophy.
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PMID:Inhibition of putative hyalurosome platform in keratinocytes as a mechanism for corticosteroid-induced epidermal atrophy. 2322 47

Molecular imaging, the visualization of molecular and cellular markers, is a promising method for detection of dysplasia and early cancer in the esophagus and can potentially be used to identify regions of interest for biopsy or tumor margins for resection. EGFR is a previously reported cell surface receptor with stepwise increases in expression during the progression from Barrett's metaplasia to adenocarcinoma. In this work, a 200 nm fluorescent nanoparticle contrast agent was synthesized for targeted imaging of EGFR through a series of surface modifications to dye-encapsulated polystyrene particles. Amino-functionalized polystyrene particles were PEGylated using a heterobifunctional PEG linker. Subsequently, thiolated M225 antibodies were conjugated to maleimide functional groups on attached PEGs for EGFR targeting. In vitro binding studies using flow cytometry demonstrated specific binding of M225-PEG-NP to EGFR-expressing cells with minimal nonspecific binding in EGFR(-) cells. Binding was shown to increase proportionally with the number of conjugated M225 antibodies. Adsorbed formulations with unmodified M225 antibodies, M225 + PEG-NP, were synthesized using the same antibody feeds used in M225-PEG-NP synthesis to determine the contribution of adsorbed antibodies to EGFR targeting. Adsorbed antibodies were less efficient at mediated nanoparticle targeting to EGFR than conjugated antibodies. Finally, M225-PEG-NP demonstrated binding to EGFR-expressing regions in human esophageal tissue sections.
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PMID:Synthesis and characterization of anti-EGFR fluorescent nanoparticles for optical molecular imaging. 2327 65

Tetraiodothyroacetic acid (tetrac) and its nanoparticle formulation (Tetrac NP) act at an integrin cell surface receptor to inhibit tumor cell proliferation and tumor-related angiogenesis. Human pancreatic cancer cell (PANC-1 and MPanc96) xenografts were established in nude mice, and the effects of tetrac versus Tetrac NP on tumor growth and tumor angiogenesis were determined. The in vitro effects of tetrac and Tetrac NP were also determined by reverse transcription polymerase chain reaction or immunoblot on gene expression or gene products relevant to cell cycle arrest, apoptosis, or angiogenesis. Tetrac and Tetrac NP reduced both PANC-1 tumor mass by 45-55 % and PANC-1 tumor hemoglobin content, a marker of angiogenesis, by 50-60 % (*P < 0.05) in treated groups vs. controls by treatment day 15. Comparable results were obtained with tetrac and Tetrac NP in suppressing tumor growth and tumor angiogenesis in MPanc96 xenografts. In vitro studies showed that tetrac and Tetrac NP caused accumulation of pro-apoptotic protein BcLx-s. Tetrac NP was more effective than tetrac in increasing cellular abundance of mRNAs of pro-apoptotic p53 and p21 and anti-angiogenesis thrombospondin 1 protein in PANC-1 and MPanc96 cancer cell lines. Tetrac NP noticeably decreased expression of EGFR and of anti-apoptosis gene XIAP; tetrac did not affect EGFR and increased XIAP mRNA in both MPanc96 and PANC-1. In conclusion, tetrac or Tetrac NP effectively inhibited human pancreatic xenograft growth and tumor angiogenesis via a plasma membrane receptor that downstream modulated cellular abundance of proteins or mRNAs relevant to apoptosis and angiogenesis.
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PMID:Response of human pancreatic cancer cell xenografts to tetraiodothyroacetic acid nanoparticles. 2345 90

Natural products have served as structural resources in the history of drug discovery for cancer therapy. Among these natural products, Korean Panax ginseng serves as a potential anti-cancer medicinal plant. To determine the anti-cancer activities of Korean P. ginseng active compounds, we performed pharmacophore-based virtual screening and molecular docking studies on EGFR (epidermal growth factor receptor) tyrosine kinase domain. The EGFR family tyrosine kinase receptor is a cell surface receptor that regulates diverse biological processes including cell proliferation, differentiation, survival, and apoptosis. Over expression of EGFR tyrosine kinase domain associated with the development and progression of numerous human cancers. In our study, we developed the best pharmacophore model (Hypo1) using a diverse training set and validated by Fischer's randomization, a test set, and a decoy set. The best validated model was employed in the virtual screening of P. ginseng compound database. Further, chosen molecules were evaluated by applying ADMET screening and molecular docking studies. Finally, 14 compounds were obtained based on binding affinity scores and interactions with protein active site residues. These final lead compounds from P. ginseng can be used in the designing of new EGFR tyrosine kinase inhibitors.
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PMID:Computer-aided identification of EGFR tyrosine kinase inhibitors using ginsenosides from Panax ginseng. 2366 55

Tetraspanins are a heterogeneous group of 4-transmembrane proteins that segregate into so-called tetraspanin-enriched microdomains (TEMs) along with other cell surface proteins such as integrins. TEMs of various types are reportedly involved in the regulation of cell growth, migration and invasion of several tumour cell types, both as suppressors or supporting structures. Tetraspanin 1 (Tspan1, NET-1), a member of the transmembrane 4 superfamily (TM4SF) of tetraspanins, is overexpressed in high-grade cervical intraepithelial neoplasia (CIN) and terminal carcinomas but its precise function in the context of carcinoma of the cervix uteri is not known. Here, we present a comprehensive investigation of the role of tetraspanin 1 in the cervical cancer cell lines SiHa and HeLa. We document that tetraspanin 1 increases the invasive potential of cervical cancer cells, whereas proliferation, growth in soft agar and adhesion are largely unaffected. In line with the latter findings, our data exclude the participation of testraspanin in integrin-mediated activation of focal adhesion kinase (FAK), paxillin and phosphoinositide-3-kinase (PI3K) and in EGFR-dependent signalling to the Ras/Erk pathway. In conclusion, our data argue against a role for tetraspanin 1 as a genuine mediator of cell surface receptor signalling but rather document a role for tetraspanin 1 in the control of cervical cancer cell motility and invasion.
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PMID:Tetraspanin 1 promotes invasiveness of cervical cancer cells. 2375 16

Fibroblast growth factors (FGF) are a family of ligands that bind to four different types of cell surface receptor entitled, FGFR1, FGFR2, FGFR3 and FGFR4. These receptors differ in their ligand binding affinity and tissue distribution. The prototypical receptor structure is that of an extracellular region comprising three immunoglobulin (Ig)-like domains, a hydrophobic transmembrane segment and a split intracellular tyrosine kinase domain. Alternative gene splicing affecting the extracellular third Ig loop also creates different receptor isoforms entitled FGFRIIIb and FGFRIIIc. Somatic fibroblast growth factor receptor (FGFR) mutations are implicated in different types of cancer and germline FGFR mutations occur in developmental syndromes particularly those in which craniosynostosis is a feature. The mutations found in both conditions are often identical. Many somatic FGFR mutations in cancer are gain-of-function mutations of established preclinical oncogenic potential. Gene amplification can also occur with 19-22% of squamous cell lung cancers for example having amplification of FGFR1. Ontologic comparators can be informative such as aberrant spermatogenesis being implicated in both spermatocytic seminomas and Apert syndrome. The former arises from somatic FGFR3 mutations and Apert syndrome arises from germline FGFR2 mutations. Finally, therapeutics directed at inhibiting the FGF/FGFR interaction are a promising subject for clinical trials.
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PMID:Fibroblast growth factor receptors, developmental corruption and malignant disease. 2388 Mar 3

Humanized monoclonal antibodies (mAb) against HER2 are being engineered to treat cancer. We utilized phage-display technology to generate a novel anti-HER2 mAb (named 73JIgG) that binds an epitope of HER2 distinct from that of trastuzumab. Although these mAbs bind to the same cell surface receptor, they have different cell distribution profiles. After 3h of incubation, almost 10% of the total 73JIgG reaches the lysosome compared to less than 3% of trastuzumab. Interestingly, 73JIgG disassociates from HER2 whereas trastuzumab remains bound to the receptor. Importantly, HER2 distribution is not affected by the antibody binding epitope, thus negating this mechanism as the reason for the difference in intracellular trafficking of 73JIgG versus trastuzumab. Each of trastuzumab and 73JIgG was chemically-modified with either a small molecule or polymeric nanoparticle to better understand the influence of conjugation on cellular localization. Relative to antibody alone, antibody-nanoparticle conjugates resulted in a higher concentration of antibodies in the lysosome whereas antibody-small molecule conjugates did not affect cell trafficking to the lysosome. Given the importance of lysosomal targeting, these results demonstrate the importance of understanding the influence of the antibody-conjugate on cell trafficking for ultimate optimization of treatment selection.
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PMID:Targeting HER2+ breast cancer cells: lysosomal accumulation of anti-HER2 antibodies is influenced by antibody binding site and conjugation to polymeric nanoparticles. 2388 Apr 72

The wide use of paclitaxel and docetaxel in NSCLC clinical treatment makes it necessary to find biomarkers for identifying patients who can benefit from paclitaxel or docetaxel. In present study, NCI-H460, a NSCLC cell line with different sensitivity to paclitaxel and docetaxel, was applied to DNA microarray expression profiling analysis at different time points of lower dose treatment with paclitaxel or docetaxel. And the complex signaling pathways regulating the drug response were identified, and several novel sensitivity-realted markers were biocomputated.The dynamic changes of responding genes showed that paclitaxel effect is acute but that of docetaxel is durable at least for 48 hours in NCI-H460 cells. Functional annotation of the genes with altered expression showed that genes/pathways responding to these two drugs were dramatically different. Gene expression changes induced by paclitaxel treatment were mainly enriched in actin cytoskeleton (ACTC1, MYL2 and MYH2), tyrosine-protein kinases (ERRB4, KIT and TIE1) and focal adhesion pathway (MYL2, IGF1 and FLT1), while the expression alterations responding to docetaxel were highly co-related to cell surface receptor linked signal transduction (SHH, DRD5 and ADM2), cytokine-cytokine receptor interaction (IL1A and IL6) and cell cycle regulation (CCNB1, CCNE2 and PCNA). Moreover, we also confirmed some different expression patterns with real time PCR. Our study will provide the potential biomarkers for paclitaxel and docetaxel-selection therapy in clinical application.
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PMID:DNA microarray reveals different pathways responding to paclitaxel and docetaxel in non-small cell lung cancer cell line. 2392 72

Approximately 15% of primary breast cancers have amplification/overexpression of the cell surface receptor HER2. Despite the major improvements in survival achieved by the use of adjuvant trastuzumab, many of these patients still develop metastatic disease, and other patients with HER2 overexpressing breast cancer have overt metastases at first diagnosis. There remains therefore a pressing medical need to identify better therapies for these patients. Pertuzumab is a humanized antibody that targets and binds HER2. Although only modestly active against breast cancer when used as a single agent, pertuzumab has demonstrated significant activity when combined with trastuzumab against trastuzumab-resistant and -sensitive disease. Multiple clinical trials are underway to define the optimal use of pertuzumab (combined with either trastuzumab or trastuzumab-DM1) together with a range of cytotoxic agents or endocrine therapy in multiple settings of HER2-overexpressing breast cancer. This article summarizes the use of pertuzumab in the metastatic disease setting.
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PMID:Pertuzumab for the treatment of metastatic breast cancer. 2398 93


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