Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We demonstrated previously that human glioblastoma cell lines accumulated heat shock protein (hsp)72, not only after heat shock, but also after, gamma-ray or UV irradiation. In the present study, we investigated whether the binding activity of heat shock transcription factor (HSF) to the heat shock element (HSE) of the hsp72 gene promoter increased after UV irradiation of human glioblastoma A-172 cells. A gel mobility-shift assay showed that the activated HSF level increased markedly after UV irradiation. Furthermore, UV irradiation of nuclear extracts in vitro did not activate HSF, whereas in vitro heat shock treatment did. These results suggest that HSF activation can be induced by UV irradiation at normal physiological temperature and hsp72 accumulation results from an increased activated HSF level, i.e. a transcriptional up-regulation of hsp72. In addition, the mechanism responsible for UV-induced HSF activation may differ from the process that operates in heat-treated cells.
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PMID:Heat shock transcription factor, HSF, is activated by ultraviolet irradiation. 897 36

The accumulation of the inducible hsp72 (72-kDa heat shock protein) after hyperthermia and/or cisplatin treatment in human glioblastoma cell line (A-172) was studied by Western blot analysis. The level of hsp72 increased to eight-fold 10 h after hyperthermia alone (44 degrees C for 20 min, D50) and to three-fold 10 h after cisplatin treatment (5 microg/ml) at 37 degrees C for 15 min (D50). In contrast, when the cells were simultaneously heated with cisplatin, the accumulation of hsp72 was suppressed. The level of hsp72 increased to about six-fold and two-fold 10 h after hyperthermia (44 degrees C, 15 min) in the presence of 1 and 10 microg/ml (D50 or D10) of cisplatin, respectively. In addition, we found both the enhancement of thermosensitivity and the suppression of thermotolerance by the simultaneously combined treatment of hyperthermia and cisplatin. It has been reported that the enhancement of cisplatin cytotoxicity by hyperthermia is due to increase of both cisplatin uptake and DNA damage by hyperthermia. Our results suggest that the interactive cytotoxic enhancement by the combination of hyperthermia and cisplatin may be also due to the suppression of heat-induced hsp72 accumulation by cisplatin.
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PMID:Suppression of heat-induced hsp72 accumulation by cisplatin in human glioblastoma cells. 901 10

We investigated the effects of a protein kinase (PK) inhibitor, H-7 (1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride), on the regulation of heat shock protein (hsp)72 gene expression in a human glioblastoma cell line (A-172) using a gel mobility-shift assay and Western blot analysis. Heat shock transcription factor 1 (HSF1) was phosphorylated immediately after heat treatment (44 degrees C, 30 min) and the phosphorylation of HSF1 was suppressed by H-7. The increase in DNA binding ability of HSFI to heat shock element (HSE) by heat shock was significantly suppressed by the addition of H-7 in a dose-dependent manner. Similarly, the accumulation of hsp72 by heat shock was suppressed by the addition of H-7 in a dose-dependent manner. Since H-7 is known to be a potent inhibitor of some PKs, especially calcium-dependent PK (PKC), cyclicAMP-dependent PK (PKA) and cyclicGMP-dependent PK (PKG), it is possible that the activation of HSF1 by phosphorylation and subsequent hsp72 gene expression are dependent on some of those PKs. The nature of H-7 as a non-specific inhibitor for PKs is discussed in relation to its availability for regulation of heat sensitivity of cells depending on cellular level of hsp72.
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PMID:The protein kinase inhibitor, H-7, suppresses heat induced activation of heat shock transcription factor 1. 1048 32

Retinoic acid (RA) has been used to induce the regression of refractory T-cell lymphoma. In vitro and in vivo studies have shown that RA exerts this effect through the induction of apoptosis. This study was designed to investigate the molecular pathway of RA-induced apoptosis in T-lymphoma cell lines.RA-induced apoptosis was verified by morphology, flow cytometry, and DNA ladder analysis. Differential display method using a combination of 12 poly(A)-anchored primers and 20 arbitrary primers was adopted for gene cloning. Total RNAs were extracted from H9 cell line at 0, 6, 12, and 24 hours after All-trans RA (ATRA) treatment and the serial expression patterns of the candidate fragments were recognized. The cloned gene fragments were then analyzed and confirmed by Northern blot analysis on H9 and SR786 cell lines.ATRA-induced apoptosis of T-cell lymphoma was protein synthesis-dependent. The execution or irreversible phase of apoptosis appeared to occur at 6-12 hours of RA treatment. Among the 60,000 arbitrarily displayed bands, 25 of 250 candidate fragments were selected for further cloning and sequencing. A total of 14 clones could be matched to known genes and were categorized into four groups: A) transcription factors: prothymosin, CA150, p78 serine/threonine kinase, IL-1beta-stimulating gene, glucocorticoid receptor, MLN64/CAB1, gastrin-binding protein, and polypeptide from glioblastoma; B) chaperone: 90 kDa heat shock protein; C) ion channel: chloride channel protein 3; and D) cytoskeleton: cytovillin2/ezrin and vimentin. Another two clones of genes were of unrecognized functions. The remaining 11 clones belonged to unmatched or novel genes. The expression of these genes varied, either upregulated or downregulated, in response to ATRA treatment.RA-induced apoptosis may involve a cascade of genes that are related to transcription regulation, stress response, housekeeping, and the execution of apoptosis. The clarification of the RA-induced apoptotic pathway will help us to understand the molecular mechanism of cancer differentiation agents.
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PMID:Retinoic acid-induced apoptotic pathway in T-cell lymphoma: Identification of four groups of genes with differential biological functions. 1114 66

The major stress-inducible heat shock protein, Hsp70, is a chaperone protein abundantly and preferentially expressed in human tumors and tumor cell lines. Owing to the ability of Hsp70 to protect cells from a wide range of apoptotic and necrotic stimuli, it has been assumed that Hsp70 may confer survival advantage to tumor cells. To investigate this hypothesis in human tumor cell lines, we generated an adenovirus expressing antisense Hsp70 (Ad.asHsp70). The effective and specific depletion of Hsp70 by Ad.asHsp70 resulted in massive cell death of all tumorigenic cell lines tested (carcinomas of breast, colon, prostate and liver as well as glioblastoma). In spite of an effective depletion of Hsp70, Ad.asHsp70 had no effect on the survival or growth of fetal fibroblasts or non-tumorigenic epithelial cells of breast or prostate. Anti-apoptotic proteins Bcl-2, Bcl-XL and CrmA as well as peptide-inhibitors of caspases, DEVD-CHO and zVAD-FMK, failed to rescue tumor cells from Ad.asHsp70-induced cell death. These results indicate that the high expression of Hsp70 is a prerequisite for the survival of human cancer cells of various origins and reveal Hsp70 as the only protein described so far whose expression is specifically needed for the survival of tumorigenic cells.
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PMID:Heat shock protein 70 is required for the survival of cancer cells. 1119 27

AlphaB-crystallin is a developmentally regulated small heat shock protein known for its binding to a variety of denatured polypeptides and suppression of protein aggregation in vitro. Elevated levels of alphaB-crystallin are known to be associated with a number of neurodegenerative pathologies such as Alzheimer disease and multiple sclerosis. Mutations in alphaB-crystallin gene have been linked to desmin related cardiomyopathy and cataractogenesis. The physiological function of this protein, however, is unknown. Using discontinuous sucrose density gradient fractionation of post-nuclear supernatants, prepared from rat tissues and human glioblastoma cell line U373MG, we have identified discrete membrane-bound fractions of alphaB-crystallin, which co-sediment with the Golgi matrix protein, GM130. Confocal microscopy reveals co-localization of alphaB-crystallin with BODIPY TR ceramide and the Golgi matrix protein, GM130, in the perinuclear Golgi in human glioblastoma U373MG cells. Examination of synchronized cultures indicated that alphaB-crystallin follows disassembly of the Golgi at prometaphase and its reassembly at the completion of cytokinesis, suggesting that this small heat shock protein, with its chaperone-like activity, may have an important role in the Golgi reorganization during cell division.
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PMID:Small heat shock protein alphaB-crystallin is part of cell cycle-dependent Golgi reorganization. 1533 19

An in vitro study focusing on the effects of low-level radiofrequency (RF) fields from mobile radio base stations employing the International Mobile Telecommunication 2000 (IMT-2000) cellular system was conducted to test the hypothesis that modulated RF fields act to induce phosphorylation and overexpression of heat shock protein hsp27. First, we evaluated the responses of human cells to microwave exposure at a specific absorption rate (SAR) of 80 mW/kg, which corresponds to the limit of the average whole-body SAR for general public exposure defined as a basic restriction in the International Commission on Non-Ionizing Radiation Protection (ICNIRP) guidelines. Second, we investigated whether continuous wave (CW) and Wideband Code Division Multiple Access (W-CDMA) modulated signal RF fields at 2.1425 GHz induced activation or gene expression of hsp27 and other heat shock proteins (hsps). Human glioblastoma A172 cells were exposed to W-CDMA radiation at SARs of 80 and 800 mW/kg for 2-48 h, and CW radiation at 80 mW/kg for 24 h. Human IMR-90 fibroblasts from fetal lungs were exposed to W-CDMA at 80 and 800 mW/kg for 2 or 28 h, and CW at 80 mW/kg for 28 h. Under the RF field exposure conditions described above, no significant differences in the expression levels of phosphorylated hsp27 at serine 82 (hsp27[pS82]) were observed between the test groups exposed to W-CDMA or CW signal and the sham-exposed negative controls, as evaluated immediately after the exposure periods by bead-based multiplex assays. Moreover, no noticeable differences in the gene expression of hsps were observed between the test groups and the negative controls by DNA Chip analysis. Our results confirm that exposure to low-level RF field up to 800 mW/kg does not induce phosphorylation of hsp27 or expression of hsp gene family.
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PMID:Mobile phone base station-emitted radiation does not induce phosphorylation of Hsp27. 1700 41

The heat shock protein HSP90 serves as a chaperone for receptor protein kinases, steroid receptors, and other intracellular signaling molecules. Targeting HSP90 with ansamycin antibiotics disrupts the normal processing of clients of the HSP90 complex. The platelet-derived growth factor receptor alpha (PDGFRalpha) is a tyrosine kinase receptor up-regulated and activated in several malignancies. Here we show that the PDGFRalpha forms a complex with HSP90 and the co-chaperone cdc37 in ovarian, glioblastoma, and lung cancer cells. Treatment of cancer cell lines expressing the PDGFRalpha with the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) promotes degradation of the receptor. Likewise, phospho-Akt, a downstream target, is degraded after treatment with 17-AAG. In contrast, PDGFRalpha expression is not affected by 17-AAG in normal human smooth muscle cells or 3T3 fibroblasts. PDGFRalpha degradation by 17-AAG is inhibited by the proteasome inhibitor MG132. High molecular weight, ubiquitinated forms of the receptor are detected in cells treated with 17-AAG and MG132. Degradation of the receptor is also inhibited by a specific neutralizing antibody to the PDGFRalpha but not by a neutralizing antibody to PDGF or by imatinib mesylate (Gleevec). Ultimately, PDGFRalpha-mediated cell proliferation is inhibited by 17-AAG. These results show that 17-AAG promotes PDGFRalpha degradation selectively in transformed cells. Thus, not only mutated tyrosine kinases but also overexpressed receptors in cancer cells can be targeted by 17-AAG.
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PMID:The platelet-derived growth factor receptor alpha is destabilized by geldanamycins in cancer cells. 1707 30

Glioblastoma (GBM) is the most common type of primary brain cancer and carries a dismal prognosis primarily due to the emergence of resistance towards extant radiation, conventional and targeted chemotherapies. Although GBM resists therapy-induced apoptosis, tumors show a seemingly paradoxical propensity for florid intratumoral necrogenesis. This necrosis manifests pathologically as microscopic foci or confluent expanses of necrotic tumor. While it is now well recognized that necrosis is an active cell death process and that apoptosis and necrosis death modalities are intertwined on multiple levels, the precise molecular mechanisms and genetic elements underlying these forms of cell death in GBM remain areas of active investigation. In recent oncogenomic studies, we identified a novel GBM oncoprotein, Bcl2-Like 12 (Bcl2L12), which is significantly expressed in the majority of primary GBM tumor specimens and distantly related to canonical Bcl-2 proteins. Due to its distinctive impact on cell death signaling, Bcl2L12 phenocopies pro-necrotic and anti-apoptotic propensities of high grade glioma: Mechanistically, we determined that unlike prototypic Bcl-2 family members, Bcl2L12 does not safeguard mitochondrial membrane integrity, but instead potently inhibits apoptosis at the level of post-mitochondrial effector caspase-3/7 activation. A combination of enforced expression, RNAi-mediated extinction, co-localization and protein interaction studies revealed that Bcl2L12 inhibits caspases 3 and 7 via distinct mechanisms. Direct physical interaction underlies Bcl2L12's inhibition of caspase-7 processing, whereas Bcl2L12-induced transcriptional upregulation of the small heat shock protein alpha B-crystallin is instrumental to neutralization of caspase-3 activation. Mirroring the cellular phenotype elicited by energy depletion, genetic or pharmacologic inhibition of post-mitochondrial apoptosis signaling molecules, Bcl2L12 promotes necrogenesis in glial cells in the context of a proapoptotic stimulus establishing that it represents a novel regulator of the balance between apoptosis and necrosis in GBM.
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PMID:What drives intense apoptosis resistance and propensity for necrosis in glioblastoma? A role for Bcl2L12 as a multifunctional cell death regulator. 1876 59

Vitespen is a heat shock protein (gp96)-peptide complex purified from resected autologous tumors, developed as a means of capturing the antigenic 'fingerprint' of a specific cancer for use as a patient-specific vaccine. Vitespen has been extensively assessed in animal models, and clinically in a range of cancers, including Phase I and II trials in colorectal cancer, glioblastoma, lung cancer, melanoma and renal cell carcinoma, and two Phase III studies in melanoma and renal cell carcinoma. Vitespen has shown itself capable of inducing major histocompatibility class I-restricted immune responses in a range of tumor types, and clinical responses in patients with earlier-stage disease, in line with previously published data on cancer vaccines. Vitespen is almost devoid of side effects aside from minor injection-site reactions.
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PMID:Vitespen: a preclinical and clinical review. 1966 26


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