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)

FABP7 expression has been analysed in a series of 123 glioblastomas (68 pure GBM, 55 GBMO, i.e. with oligodendroglial component). FABP7, found in 91/123 samples, showed a pure cytoplasmic expression in 69 cases, and cytoplasmic+nuclear expression in 22 cases. FABP7 expression was associated with pure GBM histology and shorter survival (15.7 months versus 21.5 months). Nuclear expression of FABP7 was more specifically related to EGFR amplification and more invasive tumors. These data, although they need to be confirmed by further studies, support the relation between FABP7, astrocytic features, invasion and poor prognosis and suggests that EGFR amplification is associated with nuclear translocation of FABP7.
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PMID:FABP7 expression in glioblastomas: relation to prognosis, invasion and EGFR status. 1741 24

Mutations involving the TP53 gene are frequently identified in up to 50% of all human tumors, including glioblastomas. Analysis of expression patterns of TP53 in glioblastomas shows that it is mainly mutated in secondary glioblastomas and is less common in primary GBMs. However, the prognostic significance of TP53 loss of function in astrocytomas has always been controversial. In contrast, EGFR/erbB2 complexes have been implicated in the poor prognosis of several cancers, including glioblastomas. Our previous work showed that transforming phenotypes could be inhibited by interfering with active EGFR/erbB2 complex using mutant erbB2 proteins in wild-type p53 GBM cells. To assess the dependence of EGFR inhibited phenotype on p53, we used three mutant p53 glioblastoma cell lines in the present study and showed that mutant erbB2 can be exploited to inhibit EGFR-mediated oncogenic transformation irrespective of p53 status. Ectopic expression of a mutant erbB2 receptor (T691S) in mutant p53 GBM cells resulted in slower growth rate than empty vector controls. T691S-expressing clones exhibited a more flattened and nontransformed morphology. Consistently, T691S inhibited transformation in soft agar assays and tumor formation in nude mice independent of p53 status. Biochemical analysis showed reduced Akt and GSK-3 alpha/beta, but not p42/44MAPK phosphorylation, in T691S-expressing cells, when compared to parental controls, suggesting the P13-K pathway may be more relevant than MAPK for glial cell transformation. Cell cycle analysis showed reduced cyclin D1 and CDK6 and increased phospho-Cdc-2 (Tyr15) and p15INK4B in erbB2-inhibited cells, suggesting that nonfunctional EGFR/erbB2 complexes exert their inhibitory effects at various stages of the cell cycle to block the progression of cells through G2/M via Akt/GSK-3/Cdc2 pathway. Collectively, these observations provide a basis for receptor-based therapies that disable erbB receptors and inhibit proliferative signals in erbB-expressing human cancers including glioblastomas, regardless of their TP53 status.
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PMID:EGFR inhibition in glioblastoma cells induces G2/M arrest and is independent of p53. 1745 42

We have comparatively analyzed mechanisms associated with chromosomal and microsatellite instability in giant cell glioblastoma multiforme (gcGBM) and classic GBM. This included microsatellite instability (MSI), loss of expression of four major mismatch repair (MMR) proteins, aberrations of five chromosomes, EGFR copy number, and TP53 mutations. MSI was more frequent among gcGBM (30 vs. 7.8%, P = 0.054). TP53 mutations were more commonly observed in gcGBM (83.3%), whereas EGFR was amplified in just one gcGBM (8.3%). By tumor cell phenotype-specific cytogenetic analysis of gcGBM, increased chromosome copy numbers were identified in 72-84% of giant cells but in only 4-14% of nongiant cells; in classic GBM, intermediate frequencies were noted (11-49%). Chromosome 10 deletions were found in nongiant cells of all gcGBM cases but in only approximately 45% of the cell population in classic GBM. The present study shows a distinct pattern of cytogenetic alterations in nongiant and giant cell phenotypes in gcGBM and suggests that multinuclear giant cells evolve from nongiant tumor cells at an early tumor stage. Furthermore, the data point to differences in the profile of chromosomal and microsatellite instability in gcGBM and classic GBM that might underscore the distinct pathological features of both tumor subtypes.
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PMID:Cytogenetic and molecular genetic analyses of giant cell glioblastoma multiforme reveal distinct profiles in giant cell and non-giant cell subpopulations. 1749 54

The present studies defined the biological effects of a GST fusion protein of melanoma differentiation-associated gene-7 (mda-7), GST-MDA-7 (1 and 30 nmol/L), on cell survival and cell signaling in primary human glioma cells in vitro. GST-MDA-7, in a dose- and time-dependent fashion killed glioma cells with diverse genetic characteristics; 1 nmol/L caused arrest without death, whereas 30 nmol/L caused arrest and killing after exposure. Combined inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) and AKT function was required to enhance 1 nmol/L GST-MDA-7 lethality in all cell types, whereas combined activation of MEK1 and AKT was required to suppress 30 nmol/L GST-MDA-7 lethality; both effects are mediated in part by modulating c-Jun NH(2)-terminal kinase (JNK) 1-3 activity. The geldanamycin 17AAG inhibited AKT and ERK1/2 in GBM cells and enhanced GST-MDA-7 lethality. JNK1-3 signaling promoted BAX activation and mitochondrial dysfunction. In GBM6 cells, GST-MDA-7 (30 nmol/L) transiently activated p38 mitogen-activated protein kinase, which was modestly protective against JNK1-3-induced toxicity, whereas GST-MDA-7 (300 nmol/L) caused prolonged intense p38 mitogen-activated protein kinase activation, which promoted cell death. In GBM12 cells that express full-length mutant activated ERBB1, inhibition of ERBB1 did not modify GST-MDA-7 lethality; however, in U118 established glioma cells, stable overexpression of wild-type ERBB1 and/or truncated active ERBB1vIII suppressed GST-MDA-7 lethality. Our data argue that combined inhibition of ERK1/2 and AKT function, regardless of genetic background, promotes MDA-7 lethality in human primary human glioma cells via JNK1-3 signaling and is likely to represent a more ubiquitous approach to enhancing MDA-7 toxicity in this cell type than inhibition of ERBB1 function.
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PMID:Regulation of GST-MDA-7 toxicity in human glioblastoma cells by ERBB1, ERK1/2, PI3K, and JNK1-3 pathway signaling. 1828 16

Gefitinib and erlotinib are both selective EGFR tyrosine kinase inhibitors (EGFR-TKIs) that have produced responses in a small subgroup of lung cancer patients. The strongest evidence for a role of EGFR in the biology of glioblastoma stems from clinical trials in which 15-20% of recurrent glioblastoma patients experienced significant tumour regression in response to these small-molecule EGFR kinase inhibitors. We examined the protein-kinase domain of the EGFR gene, EGFR protein expression and EGFR gene amplification in 20 cases of recurrent GBMs. EGFR protein over-expression was found in 65% of cases. EGFR protein over-expression was associated with EGFR gene amplification in 35% of cases, and with high polysomy in 15% of cases. No mutations were found in the TK domain of the EGFR gene. Our results confirm that mutations in the kinase domain are absent in recurrent GBM, and this might be a preponderant factor in the lack of major clinical responses of TKIs in GBM, recent studies have suggested that responsiveness to EGFR kinase inhibitors was strongly associated with coexpression of EGFRvIII and PTEN. Further prospective validation of EGFRvIII and PTEN as predictors of the clinical response to EGFR kinase inhibitors in recurrent GBM is strongly anticipated.
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PMID:Analysis of EGFR gene amplification, protein over-expression and tyrosine kinase domain mutation in recurrent glioblastoma. 1875 56

Not all Glioblastoma multiforme (GBM, grade IV WHO) manifest the same clinical course. Different prognostic classes may arise from different morphologic and genetic profiles. The observation of oligodendroglial foci within GBM samples and their correlation with genetic alterations may predict a better prognosis. 450 patients affected by histologically proven supratentorial cerebral GBM were treated at our institutions from January 2000 to December 2006: all patients received at least subtotal surgical removal, followed by the same standard radio-chemotherapy adjuvant treatment. In a subgroup of 36 patients (8.0%) an oligodendroglial component was observed. Molecular assessment of these cases was performed and LOH for 1p, 19q and 10q, EGFR amplification and TP53 gene expression was determined. Median age of this subgroup was 52.1 years (range: 29-78 years) vs 62.4 years in the entire GBM population. Chromosome analysis resulted as follows: LOH 1p and/or 19q in 27 cases (75.0%), LOH of 10q in 21 cases (58.1%), EGFR amplification in 14 cases (39%) and TP53 mutation in eight patients (22.2%). OS was of 20.9 months while it was 13.6 months in the entire GBM population. Progression free survival (PFS) was 10.3 months and 7.6 months the entire group. Two-year survival was of 55%. The presence of an oligodendroglial component in GBM appears to be an important prognostic factor to which better prognosis can be related. LOH 1p and 19q was significantly associated with GBM with oligodendroglial component.
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PMID:Cerebral glioblastoma with oligodendrogliomal component: analysis of 36 cases. 2122 90

One of the hallmarks of glioblastoma is its inherent tendency to recur. At this point patients with relapsed GBM show a survival time of only few months. The molecular basis of the recurrence process in GBM is still poorly understood. The aim of the present study was to investigate the genetic profile of relapsed GBM compared to their respective primary tumors. We have included 20 paired GBMs. In all tumor samples, we have analyzed p53 and PTEN status by sequencing analysis, EGFR amplification by semiquantitative PCR and a wide-genome fingerprinting was performed by microsatellite analysis. Among primary GBM, we observed twelve type 2 GBM, four type 1 GBM and four further GBM showing neither p53 mutations nor EGFR amplification (non-type 1-non-type 2 GBM). Upon recurrence, we have detected two molecular patterns of tumor progression: GBM initially showing either type 1 or type 2 profiles conserved them at the time of relapse. In contrast, non-type 1-non-type 2 GBM acquired the typical pattern of type 2 GBM and harbor EGFR amplification without p53 mutation. New PTEN mutations upon relapse were only detected in type 2 GBM. Additional LOH were more frequently identified in relapses of type 2 GBM than in those showing the type 1 signature. Taken together, our results strongly suggest that recurrences of GBM may display two distinct pattern of accumulation of molecular alterations depending on the profile of the original tumor.
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PMID:Different molecular patterns in glioblastoma multiforme subtypes upon recurrence. 1964 52

A 4-year-old Dutch warmblood mare was presented with a 10-month history of ataxia and proprioceptive deficits. Computed tomography defined a large, non-contrast enhancing mass in the left cerebral hemisphere. Necropsy examination revealed a tumour that effaced much of the piriform and temporal lobes. Microscopically the lesion was classified as a grade IV glioblastoma with an oligodendroglial component (GBM-O). The tumour was composed of highly pleomorphic cells organized in different patterns within a fibrillary stroma. There were multiple foci of necrosis. At the periphery of the tumour neoplastic oligodendroglioma-like cells were embedded in an extracellular mucinous matrix. Most neoplastic cells were strongly immunoreactive for glial fibrillary acidic protein; however, the oligodendroglioma cells did not express this marker. Cells forming microvascular proliferations were positively labelled for expression of factor VIII and smooth muscle actin. All neoplastic cells were negative for Neu-N and synaptophysin. The proliferation index was up to 5%. All neoplastic cells and normal brain tissue from the horse were uniformly negative for expression of epidermal growth factor receptor (EGFR), EGFR vIII mutant and the phosphatase and tensin homologue (PTEN) compared with positive control human GBM tissue. To our knowledge this is the first report of a GBM-O in the horse.
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PMID:A grade IV glioblastoma with an oligodendroglial component (GBM-O) in a horse. 1989 10

Fifty-seven spontaneous canine gliomas were histologically classified and graded using the latest World Health Organization (WHO 2007) criteria for classification of human gliomas. A total of 19 canine astrocytomas were classified as follows: grade IV (GBM) n = 7; grade III n = 5; and grade II, n = 7. Thirty-eight oligodendrogliomas were classified as either grade III (anaplastic) n = 35 or low grade II n = 3. Tissue microarray (TMA) immunohistochemistry was used to evaluate tumor expression of EGFR, PDGFRa and IGFBP2, three key molecules of known pathophysiological importance in human gliomas. Findings were correlated with tumor classification and grade. Increased EGFR expression was demonstrated in 57% of GBMs, 40% of grade III and 28% of grade II astrocytomas. EGFR expression occurred in only 3% of grade III oligodendrogliomas. Increased expression of PDGFRalpha was demonstrated in 43% of GBMs, 20% of grade III, and 14% of grade II astrocytomas. In the oligodendroglioma series, 94% of grade III tumors overexpressed PDGFRalpha. IGFBP2 expression was detected in 71, 60 and 28% of GBMs, grade III and grade II astrocytomas respectively. IGFBP2 expression occurred in 48% of anaplastic and in 33% of low grade oligodendrogliomas. Expression of EGFR, PDGFRalpha or IGFBP2 was not detected in normal canine CNS control TMA cores. The incidence of overexpression of EGFR, PDGFRalpha and IGFBP2 in these canine gliomas closely parallels that in human tumors of similar type and grade. These findings support a role for the spontaneous canine glioma model in directed pathway-targeting therapeutic studies.
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PMID:Spontaneous canine gliomas: overexpression of EGFR, PDGFRalpha and IGFBP2 demonstrated by tissue microarray immunophenotyping. 1996 49

Glioblastoma, GBM, is the most frequent brain malignancy in adults. Patients with these tumors survive only, approximately, one year after diagnosis and rarely survive beyond two years. This poor prognosis is, in part, due to our insufficient understanding of the complex aggressive nature of these tumors and the lack of effective therapy. In GBM, over-expression of EGFR and/or its constitutively activated variant EGFRvIII is a major characteristic and is associated with tumorigenesis and more aggressive phenotypes, such as, invasiveness and therapeutic resistance. Consequently, both have been major targets for GBM therapy, however, clinical trials of EGFR- and EGFRvIII-targeted therapies have yielded unsatisfactory results and the molecular basis for the poor results is still unclear. Thus, in this review, we will summarize results of recent clinical trials and recent advances made in the understanding of the EGFR/EGFRvIII pathways with a key focus on those associated with intrinsic resistance of GBM to EGFR-targeted therapy. For example, emerging evidence indicates an important role that PTEN plays in predicting GBM response to EGFR-targeted therapy. Aberrant Akt/mTOR pathway has been shown to contribute to the resistant phenotype. Also, several studies have reported that EGFR/EGFRvIII's cross-talk with the oncogenic transcription factorSTAT3 and receptor tyrosine kinases, (c-Met and PDGFR) potentially lead to GBM resistance to anti-EGFR therapy. Other emerging mechanisms, including one involving HMG-CoA reductase, will also be discussed in this mini-review. These recent findings have provided new insight into the highly complex and interactive nature of the EGFR pathway and generated rationales for novel combinational targeted therapies for these tumors.
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PMID:EGFR-targeted therapy in malignant glioma: novel aspects and mechanisms of drug resistance. 2003 Jun 24


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