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)

Larvae of Galleria mellonella exposed to mild heat-shock (38 degrees C) showed an enhanced humoral immune response after microbial infection in comparison to infected animals grown at 28 degrees C. This enhanced response was manifested by increased expression of antimicrobial peptide (AMP) genes leading to enhanced antimicrobial activity in the hemolymph. We found an increased level of Hsp90 and changes in the level of a 55kDa protein recognized by anti-Hsp90 antibodies in fat bodies of infected animals reared at 28 degrees C as well as in uninfected animals exposed to elevated temperature. Pre-treatment of animals with an inhibitor of Hsp90, 17-DMAG, prior to immunization resulted in increased expression of AMP genes encoding gallerimycin and cecropin at 38 degrees C. This observation was correlated with the changes in Hsp90 protein and increased level of 55kDa protein. Also G. mellonella larvae pre-treated with 17-DMAG and exposed to mild heat-shock for 30min showed an increased survival rate after infection with entomopathogenic bacteria Pseudomonas aeruginosa. We also show the effect of 17-DMAG on the phosphorylation state of ERK MAP kinase. We postulate that Hsp90 may play a significant role in converging pathways involved in the insect immune response and heat-shock.
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PMID:Humoral immune response upon mild heat-shock conditions in Galleria mellonella larvae. 1763 8

Hsp90 inhibitors are currently in clinical trials for cancer therapy based on their ability to promote proteasomal degradation of oncogenic protein kinases and nuclear receptors. Results from recent studies suggest that cancer cells are more sensitive to these inhibitors than cells from healthy tissues. We analyzed an immortalized cell line Ba/F3 for sensitivity to the Hsp90 inhibitor geldanamycin in the absence and presence of the oncogenic tyrosine fusion kinase NPM-ALK expressed from a retroviral vector. Our results showed that NPM-ALK expression makes Akt and Cdk4 more resistant to degradation in the presence of geldanamycin, and there was a slightly reduced amount of apoptosis. The mechanism underlying the effect of NPM-ALK on Akt stability was probed by comparison of the turnover of the kinase after translation inhibition and geldanamycin treatment. We observed that Akt was degraded more rapidly in the presence of GA than upon translation inhibition without NPM-ALK expression. This suggests that NPM-ALK protects the mature kinase. Furthermore, Akt failed to bind to the Cdc37 chaperone in cells expressing NPM-ALK, which also correlates with increased Akt stability.
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PMID:Akt shows variable sensitivity to an Hsp90 inhibitor depending on cell context. 1764 29

Hop/STI1 is a co-chaperone adaptor protein for Hsp70/Hsp90 complexes. Hop/STI1 is found extracellularly and modulates cell death and differentiation through interaction with the prion protein (PrP(C)). Here, we investigated the expression of hop/STI1 and its role upon cell proliferation and cell death in the developing retina. Hop/STI1 is more expressed in developing rat retina than in the mature tissue. Hop/STI1 blocks retinal cell death in the neuroblastic layer (NBL) in a PrP(C) dependent manner, but failed to protect ganglion cells against axotomy-induced cell death. An antibody raised against hop/STI1 (alpha-STI1) blocked both ganglion cell and NBL cell death independent of PrP(C). cAMP/PKA, ERK, PI3K and PKC signaling pathways were not involved in these effects. Hop/STI1 treatment reduced proliferation, while alpha-STI1 increased proliferation in the developing retina, both independent of PrP(C). We conclude that hop/STI1 can modulate both proliferation and cell death in the developing retina independent of PrP(C).
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PMID:Hop/STI1 modulates retinal proliferation and cell death independent of PrPC. 1765 90

Vascular endothelial growth factor receptors (VEGFRs) perform pivotal roles in both tumor growth and angiogenesis. In this study, we report that histone deacetylase inhibitors (HDIs) induce a reduction in VEGFR1 and VEGFR2 protein expression via the inhibition of class II histone deacetylases (HDACs) in human cancer cell lines. After HDI treatment, VEGFR1 and VEGFR2 were shown to be downregulated in a proteasome-dependent manner. HDI treatment induced a reduction in the binding of heat shock protein (Hsp) 90 to VEGFR1 or VEGFR2, followed by an increase of the binding of Hsp70 to VEGFR1 or VEGFR2. However, we noted no remarkable changes in the binding of Hsp90/Hsp70 to VEGFR3. HDI treatment effectively inhibited the activities of HDAC6 and HDAC10. Furthermore, the knock-down of HDAC6 or HDAC10, which was accomplished via the siRNA transfection, induced depletion of VEGFR1 or VEGFR2 proteins. Overall, these results indicate that HDAC6 and HDAC10 play important roles in Hsp-mediated VEGFR regulation.
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PMID:Class II histone deacetylases play pivotal roles in heat shock protein 90-mediated proteasomal degradation of vascular endothelial growth factor receptors. 1821 8

Molecules specifically designed to modulate protein-protein interactions have tremendous potential as novel therapeutic agents. One important anticancer target is the chaperone Hsp90, whose activity is essential for the folding of many oncogenic proteins, including HER2, IGFIR, AKT, RAF-1, and FLT-3. Here we report the design and characterization of new tetratricopeptide repeat modules, which bind to the C-terminus of Hsp90 with higher affinity and with greater specificity than natural Hsp90-binding co-chaperones. Thus, when these modules are introduced into the cell, they out-compete endogenous co-chaperones for binding, thereby inhibiting Hsp90 function. The effect of Hsp90 inhibition in this fashion is dramatic; HER2 levels are substantially decreased and BT474 HER2 positive breast cancer cells are killed. Our designs thus provide new tools with which to dissect the mechanism of Hsp90-mediated protein folding and also open the door to the development of an entirely new class of anticancer agents.
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PMID:Designed TPR modules as novel anticancer agents. 1835 5

HER-2 is a tyrosine kinase receptor which is overexpressed in 20-25% of breast cancer patients and is associated with poor prognosis. Trastuzumab, a humanized monoclonal antibody directed against the HER-2 receptor, used alone or in combination with chemotherapy, has shown significant clinical benefit in improving survival in metastatic patients, as well as halving the recurrence rate and improving survival in early breast cancer. Even with these impressive results, the reality is that not all patients will benefit form this therapy, and in those who do, resistance to trastuzumab can often develop within 1 year of treatment initiation. Beyond trastuzumab therapy, a "second wave" of monoclonal antibodies and tyrosine kinase inhibitors has emerged. These drugs have variable properties including: 1) dual inhibition against EGFR and HER-2, such as lapatinib, HKI-272 and pertuzumab; 2) anti-angiogenesis such as bevacizumab and pazopanib; 3) anti-mTOR action such as Temsirolimus; and 4) anti-Hsp90 such as 17-AAG. When used in combination with trastuzumab, or with cytotoxic chemotherapy, or as single agents, these new anti-HER-2 strategies bear the potential of arresting the tumorigenesis process. In this article, we present the current strategies in the treatment of breast cancer patients who overexpress HER-2, with particular focus on new tyrosine kinase inhibitors that can be used in combination with or after trastuzumab therapy.
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PMID:HER-2 positive breast cancer: what else beyond trastuzumab-based therapy? 1853 32

Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant central nervous system neoplasm that usually affects infants and young children. In this report, we describe culture conditions that enabled the sustained growth of tumor cells obtained from the cerebrospinal fluid (CSF) of an infant with AT/RT. These cells retained the morphological and biomarker characteristics of the original tumor. A screening of receptor tyrosine kinases identified the presence of phosphorylated ErbB4, Insulin-R, PDGFR and IGF-IR, which appear to depend on Hsp90 to maintain their active form. IGF-IR activity is consistent with data from other established AT/RT cell lines. Inhibition of IGF-IR by the small molecular weight inhibitor AEW541 led to growth suppression of cultured AT/RT cells. In addition, neutralizing antibodies to IGF-II also inhibited the growth of these cells suggesting a potential autocrine function for this cytokine. We also compared cultured AT/RT cells to established cell lines to identify consistent drug sensitivity patterns among these cells. In addition to previously described cell lines and xenograft models, continuous culture of CSF derived cells may also provide an effective way to study the biology of AT/RT and to identify potential targets for future therapeutics for this tumor.
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PMID:Establishment of atypical-teratoid/rhabdoid tumor (AT/RT) cell cultures from disseminated CSF cells: a model to elucidate biology and potential targeted therapeutics. 1865 Nov 3

Her-2/neu (ErbB2) is a transmembrane tyrosine kinase and acts as a co-receptor for the other EGFR family members. It is well known that high expression of Her-2/neu is associated with a poor prognosis in breast cancer. Quercetin, a flavonoid present in many vegetables and fruits, has been studied extensively as a chemoprevention agent in several cancer models. In this study, we observed that quercetin decreased the level of Her-2/neu protein in time- and dose-dependent manners and also inhibited the downstream survival PI3K-Akt signaling pathway in Her-2/neu-overexpressing breast cancer SK-Br3 cells. We also observed that quercetin induced polyubiquitination of Her-2/neu. When the proteasome pathway was blocked by MG-132 during quercetin treatment, accumulation of the NP-40 insoluble form of Her-2/neu occurred. Interestingly, data from immunocomplex studies revealed that quercetin promoted interaction between Her-2/neu and Hsp90 which is a molecular chaperone involved in stabilization of Her-2/neu. In this condition, inhibition of Hsp90 activity by a specific inhibitor, geldanamycin (GA), or intracellular ATP depletion caused dissociation of Hsp90 from Her-2/neu and promoted ubiquitination and down-regulation of Her-2/neu protein. In addition, the carboxyl terminus of Hsc70-interacting protein (CHIP), a chaperone-dependent E3 ubiquitin ligase, played a crucial role in the quercetin-induced ubiquitination of Her-2/neu. Inhibition of tyrosine kinase activity of Her-2/neu by quercetin could indicate an lateration in the Her-2/neu structure which promotes CHIP recruitments and down-regulation of Her-2/neu. We believe that by using quercetin, new therapeutic strategies can be developed to treat Her-2/neu overexpressing cancers.
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PMID:Quercetin-induced ubiquitination and down-regulation of Her-2/neu. 1865 87

Adult human bone marrow stromal cells (BMSCs) containing or consisting of mesenchymal stem cells (MSCs) are an important source in tissue homeostasis and repair. Although many processes involved in their differentiation into diverse lineages have been deciphered, substantial inroads remain to be gained to synthesize a complete regulatory picture. The present study suggests that structural conformation of extracellular collagen I, the major organic matrix component in musculoskeletal tissues, plays, along with differentiation stimuli, a decisive role in the selection of differentiation lineage. It introduces a novel concept which proposes that structural transition of collagen I matrix regulates cell differentiation through distinct signaling pathways specific for the structural state of the matrix. Thus, on native collagen I matrix inefficient adipogenesis is p38-independent, whereas on its denatured counterpart, an efficient adipogenesis is primarily regulated by p38 kinase. Inversely, osteogenic differentiation occurs efficiently on native, but not on denatured collagen I matrix, with a low commencement threshold on the former and a substantially higher one on the latter. Osteogenesis on collagen I matrices in both structural conformations is fully dependent on ERK. However, whereas on native collagen I matrix osteogenic differentiation is Hsp90-dependent, on denatured collagen I matrix it is Hsp90-independent. The matrix conformation-mediated regulation appears to be one of the mechanisms determining differentiation lineage of BMSCs. It allows a novel interpretation of the bone remodeling cycle, explains the marked physiological aging-related adipogenic shift in musculoskeletal tissues, and can be a principal contributor to adipogenic shift seen in a number of clinical disorders.
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PMID:Progression of human bone marrow stromal cells into both osteogenic and adipogenic lineages is differentially regulated by structural conformation of collagen I matrix via distinct signaling pathways. 1937 3

Previously, we reported that the conformational transition of collagen I matrix plays, along with differentiation stimuli, a regulatory role in determination of differentiation lineage of bone marrow stromal sells via distinct signaling pathways specific for the structural state of the matrix. The present study addresses mechanisms underlying differential structural conformation-specific effects of collagen matrices on differentiation into diverse lineages. The results obtained suggest that the pivotal player in the observed matrix conformation-mediated regulation is a differential cellular stress response elicited by the exposure to native but not to denatured collagen I matrix. The stress causing such a response appears to be generated by matrix contraction and mediated by Alpha2Beta1 integrins engaged on native but not on denatured collagen I matrix. The principal facet of the observed phenomenon is not the nature of a stress but general stress response: when cells on denatured collagen I matrix are subjected to thermal stress, osteogenic pathway shifts to that seen on native collagen I matrix. Importantly, cellular stress response might be commonly involved in determination of differentiation lineage. Indeed, distinct components of cellular stress response machinery appear to regulate differentiation into diverse lineages. Thus, augmentation of Hsp90 levels enables the operation of efficient Alpha1Beta1/Alpha2Beta1 integrin-driven ERK activation pathways hence facilitating osteogenesis and suppressing adipogenesis, whereas myogenesis of satellite stem cells appears to be promoted by native collagen I matrix-elicited activation and nuclear translocation of another stress response component, Beta-catenin, shown to be essential for skeletal myogenesis, and chondrogenesis may involve stress-mediated elevation of yet another stress response constituent, Hsp70, shown to be an interactive partner of the chondrogenic transcription factor SOX9. The proposed concept of the integral role of cellular stress response in tissue generation and maintenance suggests new therapeutic approaches and indicates novel tissue engineering strategies.
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PMID:Collagen I matrix contributes to determination of adult human stem cell lineage via differential, structural conformation-specific elicitation of cellular stress response. 1937 6


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