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: UMLS:C0017636 (glioblastoma)
18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Despite the strikingly grave prognosis for older patients with glioblastomas, significant variability in patient outcome is experienced. To explore the potential for developing improved prognostic capabilities based on the elucidation of potential biological relationships, we did analyses of genes commonly mutated, amplified, or deleted in glioblastomas and DNA microarray gene expression data from tumors of glioblastoma patients of age >50 for whom survival is known. No prognostic significance was associated with genetic changes in epidermal growth factor receptor (amplified in 17 of 41 patients), TP53 (mutated in 11 of 41 patients), p16INK4A (deleted in 15 of 33 patients), or phosphatase and tensin homologue (mutated in 15 of 41 patients). Statistical analysis of the gene expression data in connection with survival involved exploration of regression models on small subsets of genes, based on computational search over multiple regression models with cross-validation to assess predictive validity. The analysis generated a set of regression models that, when weighted and combined according to posterior probabilities implied by the statistical analysis, identify patterns in expression of a small subset of genes that are associated with survival and have value in assessing survival risks. The dominant genes across such multiple regression models involve three key genes-SPARC (Osteonectin), Doublecortex, and Semaphorin3B-which play key roles in cellular migration processes. Additional analysis, based on statistical graphical association models constructed using similar computational analysis methods, reveals other genes which support the view that multiple mediators of tumor invasion may be important prognostic factor in glioblastomas in older patients.
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PMID:Gene expression profiling and genetic markers in glioblastoma survival. 1589 94

Inactivating mutations in the tumor suppressor gene phosphatase and tensin homologue on chromosome 10 (PTEN) result in elevated levels of phosphatidylinositol (3,4,5)-trisphosphate, activation of protein kinase B (PKB), and protection against apoptotic insults such as withdrawal of survival factors. Protection may arise through the inhibition of the pro-apoptotic protein Bim, which is normally repressed by a PKB-dependent mechanism. Here we show that PTEN-/- immortalized mouse embryonic fibroblasts (MEFs) exhibit elevated PKB phosphorylation and are resistant to serum withdrawal-induced death, but exhibit normal Bim expression following withdrawal of serum. In contrast, expression of Mcl-1, a prosurvival member of the Bcl-2 family, was elevated in PTEN-/- MEFs. Transient or stable overexpression of Mcl-1 in PTEN+/- MEFs conferred resistance to serum withdrawal, whereas ablating expression of Mcl-1 in PTEN-/- MEFs, using RNA interference, abolished their resistance to serum withdrawal-induced apoptosis. To determine if Mcl-1 is selected for overexpression in human tumors we examined human glioblastoma cell lines but found that loss of PTEN had no effect on Mcl-1 expression. In contrast, two of three PTEN-/- glioblastoma cell lines exhibited low expression of Bim, which was refractory to serum withdrawal. These results indicate that the resistance of PTEN-/- MEFs to serum withdrawal is largely due to the up-regulation of Mcl-1 but that loss of PTEN in tumor cell lines is more complex and may favor de-regulation of different apoptotic regulators such as Bim.
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PMID:Increased expression of Mcl-1 is required for protection against serum starvation in phosphatase and tensin homologue on chromosome 10 null mouse embryonic fibroblasts, but repression of Bim is favored in human glioblastomas. 1605 96

Frequent loss of heterozygosity (LOH) and mutations of the tumor suppressor gene PTEN (phosphatase and tensin homologue deleted from chromosome 10) have been found in sporadic gliomas. The most documented regions of allelic losses include 9p21, 10q23-25 and 17p1 3 whereas PTEN aberrations are preferentially found in glioblastoma multiformes. This research aimed to detect the incidence of allelic losses on chromosomes 10q, 9p, 17p and 13q and mutations on exons 5, 6 and 8 of PTEN in malignant gliomas. Malignant glioma specimens obtained were classified histopathologically according to the WHO criteria. Each tumor was then subjected to polymerase chain reaction (PCR)-LOH analysis using microsatellite markers and single-stranded conformational polymorphism (SSCP) analysis. Twelve of 23 (52%) malignant glioma cases showed allelic losses whereas 7 of 23 (30%) samples showed aberrant band patterns and mutations of PTEN. Four of these cases showed LOH in 10q23 and mutations of PTEN. The data on LOH indicated the involvement of different genes in the genesis of glioma whereas mutations of PTEN indicated the role of PTEN tumor suppressor gene in the progression of glioma in Malay population.
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PMID:Malignant glioma: the involvement of loss of allelic heterozygosity and PTEN mutations in a group of Malay patients. 1612 50

Mutations of the 'phosphatase and tensin homologue deleted on chromosome 10' (PTEN/MMAC1) gene have been associated with a variety of human cancers, including prostate cancer, glioblastoma, and melanoma. The gene is thought to be one of the most frequently mutated tumour suppressor genes and inactivation of PTEN is associated with disease progression and angiogenesis. High vascularization and resistance to chemo- and radio-therapy are two well-established features of phaeochromocytomas (PCCs). Furthermore, benign and malignant PCCs are found in several PTEN knockout mouse models. This study therefore evaluated whether inactivation of PTEN may be involved in the tumourigenesis of PCC in man and whether PTEN abnormalities may help to define the malignant potential of these tumours. Tumour and germline DNA was analysed from 31 patients with apparently sporadic PCC, including 14 clinically benign and 17 malignant tumours, for loss of the PTEN gene locus, mutations in the PTEN gene, and for PTEN protein expression by immunohistochemistry. Loss of heterozygosity (LOH) analysis showed loss of PTEN in four malignant tumours (40%) and in one benign tumour (14%). However, no mutations of PTEN were observed. Immunohistochemistry showed no correlation with clinical behaviour and/or LOH status. The results indicate that inactivation of the PTEN/MMAC1 gene may play a minor role in the development of malignant phaeochromocytomas.
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PMID:PTEN gene loss, but not mutation, in benign and malignant phaeochromocytomas. 1653 14

Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and Akt are important regulators of the phosphatidylinositol 3-kinase (PI3K) pathway and thus are important to the regulation of a wide spectrum of tumor-related biological processes. Akt regulates several critical cellular functions, including cell cycle progression; cell migration, invasion, and survival; and angiogenesis. Decreased expression of PTEN and overexpression of the Akt proto-oncogene, which is located downstream of PI3K, have been shown in a variety of cancers, including glioblastoma. Novel small-molecule inhibitors of receptors and signaling pathways, including inhibitors of the PI3K pathway, have shown antitumor activity, but inhibitors of Akt have not been examined. In this study, we tested our hypothesis that the pharmacologic inhibition of Akt has an antiproliferative effect on gliomas. We showed that two newly developed Akt inhibitors, KP-372-1 and KP-372-2 (herein called KP-1 and KP-2), effectively inhibited the PI3K/Akt signaling cascade. KP-1 and KP-2 blocked both the basal and epidermal growth factor-induced phosphorylation of Akt Ser473 at 125 and 250 nmol/L, which, in turn, reduced the activation of intracellular downstream targets of Akt, including GSK-3beta and p70s6k. Furthermore, the treatment of U87 and U251 glioma cells with 125 to 250 nmol/L KP-1 and KP2 for 48 hours inhibited cell growth by approximately 50%. This decrease in cell growth stemmed from the induction of apoptosis. Collectively, these results provide a strong rationale for the pharmacologic targeting of Akt for the treatment of gliomas.
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PMID:Inhibition of Akt survival pathway by a small-molecule inhibitor in human glioblastoma. 1654 78

The phosphoinositide 3-kinase (PI3K)/Akt pathway is commonly activated in cancer; therefore, we investigated its role in hypoxia-inducible factor-1alpha (HIF-1alpha) regulation. Inhibition of PI3K in U87MG glioblastoma cells, which have activated PI3K/Akt activity secondary to phosphatase and tensin homologue deleted on chromosome 10 (PTEN) mutation, with LY294002 blunted the induction of HIF-1alpha protein and its targets vascular endothelial growth factor and glut1 mRNA in response to hypoxia. Introduction of wild-type PTEN into these cells also blunted HIF-1alpha induction in response to hypoxia and decreased HIF-1alpha accumulation in the presence of the proteasomal inhibitor MG132. Akt small interfering RNA (siRNA) also decreased HIF-1alpha induction under hypoxia and its accumulation in normoxia in the presence of dimethyloxallyl glycine, a prolyl hydroxylase inhibitor that prevents HIF-1alpha degradation. Metabolic labeling studies showed that Akt siRNA decreased HIF-1alpha translation in normoxia in the presence of dimethyloxallyl glycine and in hypoxia. Inhibition of mammalian target of rapamycin (mTOR) with rapamycin (10-100 nmol/L) had no significant effect on HIF-1alpha induction in a variety of cell lines, a finding that was confirmed using mTOR siRNA. Furthermore, neither mTOR siRNA nor rapamycin decreased HIF-1alpha translation as determined by metabolic labeling studies. Therefore, our results indicate that Akt can augment HIF-1alpha expression by increasing its translation under both normoxic and hypoxic conditions; however, the pathway we are investigating seems to be rapamycin insensitive and mTOR independent. These observations, which were made on cells grown in standard tissue culture medium (10% serum), were confirmed in PC3 prostate carcinoma cells. We did find that rapamycin could decrease HIF-1alpha expression when cells were cultured in low serum, but this seems to represent a different pathway.
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PMID:Akt1 activation can augment hypoxia-inducible factor-1alpha expression by increasing protein translation through a mammalian target of rapamycin-independent pathway. 1684 22

Mutations in the MMAC/PTEN (phosphatase and tensin homologue deleted on chromosome 10) gene are documented in cancers of the breast, prostate, ovary, colon, melanoma, glioblastoma, lymphoma and endometrium. In the present work MMAC/PTEN gene expression in women with endometrial adenocarcinoma (n=70) in RNA samples obtained from cancer tissue were investigated. Control DNA was obtained from 68 normal endometrial tissue. The MMAC/PTEN expression was determined by RT-PCR analysis. The expression of MMAC/PTEN gene in endometrial adenocarcinoma cases was significantly reduced compared to the expression in the normal samples (P < 0.05). Furthermore the significant difference (P < 0.05) was observed between the expression of MMAC/PTEN in stage III versus lower stages of endometrial cancer. The results support the hypothesis that the MMAC/PTEN gene expression may be associated with the incidence of endometrial cancer.
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PMID:MMAC/PTEN gene expression in endometrial cancer: RT-PCR studies. 1721 40

Although PTEN (phosphatase and tensin homologue deleted on chromosome 10) is one of the most commonly mutated tumour suppressors in human cancers, loss of PTEN expression in the absence of mutation appears to occur in an even greater number of tumours. PTEN is phosphorylated in vitro on Thr366 and Ser370 by GSK3 (glycogen synthase kinase 3) and CK2 (casein kinase 2) respectively, and specific inhibitors of these kinases block these phosphorylation events in cultured cells. Although mutation of these phosphorylation sites did not alter the phosphatase activity of PTEN in vitro or in cells, blocking phosphorylation of Thr366 by either mutation or GSK3 inhibition in glioblastoma cell lines led to a stabilization of the PTEN protein. Our data support a model in which the phosphorylation of Thr366 plays a role in destabilizing the PTEN protein.
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PMID:PTEN is destabilized by phosphorylation on Thr366. 1744 18

Glioblastomas are malignant brain tumors that are very difficult to cure, even with aggressive therapy consisting of surgery, chemotherapy, and radiation. Glioblastomas frequently have loss of the phosphatase and tensin homologue (PTEN), leading to the activation of the phosphoinositide-3-kinase (PI3K)/Akt pathway. We examined whether PTEN deficiency leads to radioresistance and whether this can be reversed by nelfinavir, a protease inhibitor that decreases Akt signaling. Nelfinavir decreased Akt phosphorylation and enhanced radiosensitization in U251MG and U87MG glioblastoma cells, both of which are PTEN deficient. In the derivative line U251MG-PTEN, induction of wild-type PTEN with doxycycline decreased P-Akt expression and increased radiosensitivity to a similar extent as nelfinavir. Combining these two approaches had no greater effect on radiosensitivity than either alone. This epistasis-type analysis suggests that the nelfinavir acts along the Akt pathway to radiosensitize cells. However, nelfinavir neither decreased Akt phosphorylation in immortalized human astrocytes nor radiosensitized them. Radiosensitization was also assessed in vivo using a tumor regrowth delay assay in nude mice implanted with U87MG xenografts. The mean time to reach 1,000 mm(3) in the radiation + nelfinavir group was 71 days, as compared with 41, 34, or 45 days for control, nelfinavir alone, or radiation alone groups, respectively. A significant synergistic effect on tumor regrowth was detected between radiation and nelfinavir. (P = 0.01). Nelfinavir also increased the sensitivity of U251MG cells to temozolomide. These results support the clinical investigation of nelfinavir in combination with radiation and temozolomide in future clinical trials for patients with glioblastomas.
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PMID:Phosphatase and tensin homologue deficiency in glioblastoma confers resistance to radiation and temozolomide that is reversed by the protease inhibitor nelfinavir. 1748 62

Radiation therapy is a mainstay in the treatment of glioblastomas, but these tumors are often associated with radioresistance. Activation of the phosphatidylinositol-3-OH kinase (PI3K)/Akt pathway, which occurs frequently in glioblastomas due to inactivation of the tumor suppressor phosphatase and tensin homologue (PTEN), correlates with radioresistance. To directly test the link between Akt activation and radioresistance, we utilized PTEN-deficient U251 glioblastoma cells engineered to inducibly restore PTEN upon exposure to doxycycline. These cells showed high basal levels of Akt activation (i.e. high levels of phospho-Akt), but induction of PTEN led to substantially decreased phospho-Akt and was associated with radiosensitization. To investigate whether the PTEN-induced radiosensitization was attributable to impaired sensing versus repair of DNA damage, we assessed levels of gamma-H2AX after ionizing radiation in U251 cells induced for PTEN. Initial post-radiation levels of gamma-H2AX foci were not decreased in PTEN-induced cells; however, the resolution of these foci was significantly delayed. In contrast to these results, induction of phosphatase-dead PTEN showed no appreciable effect. Finally, exposure of cells to the PI3K inhibitor LY294002 did not decrease the occurrence of gamma-H2AX foci after irradiation but did markedly delay their resolution. These results together support a direct link between Akt activation, repair of DNA damage, and radioresistance in glioblastoma. Targeting the PI3K/Akt pathway may modulate DNA repair to improve the efficacy of radiation therapy.
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PMID:Inhibition of phosphatidylinositol-3-OH kinase/Akt signaling impairs DNA repair in glioblastoma cells following ionizing radiation. 1751 97


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