Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The INK4a-ARF locus encodes 2 separate proteins through differential splicing of alternative first exons to produce p16INK4a (exon 1alpha) and p14ARF (exon 1beta) products in human cells. The p16INK4a protein inhibits the cyclin D-dependent kinases (CDK) that control the phosphorylation of the Rb protein and cell proliferation. The p14ARF gene product can complex with and sequester the MDM2 protein within the nucleus, thus modulating the activity of the p53 protein. Loss of p16INK4a expression would disrupt the retinoblastoma (Rb)/p16INK4a/cyclin D-dependent kinase (CDK4) pathway, whereas loss of p14ARF expression would inactivate both the Rb and p53/ MDM2/p14ARF pathways through MDM2, which can complex with either Rb or p53. Loss of the p16INK4a gene on 9p21 has been documented in a wide range of human tumors, including one third of glioblastomas. However, in tumors showing homozygous loss of exon 2 of the p16INK4a gene, loss of exon 1beta of the p14ARF gene has not been established. In this study, we have assessed deletion of the p14ARF gene in 29 pediatric and 107 adult high-grade astrocytomas and 9 glioma cell lines, using multiplex PCR analysis for exon 1beta. We found homozygous deletions for exon 1alpha and exon 1beta in 3 of 29 (10%) of the pediatric cases (2 grade III, 1 grade IV), 25 of 107 (23%) of the adult cases (6 grade III and 19 grade IV), and 8 of 9 (89%) of the glioma cell lines. Therefore, loss of the INK4a-ARF locus in high-grade astrocytomas may contribute to the highly malignant behavior and treatment resistance of these tumors through elimination of multiple checkpoint cell cycle control proteins.
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PMID:Incidence of p14ARF gene deletion in high-grade adult and pediatric astrocytomas. 1066 22

Epidemiological studies suggest that some familial aggregations of glioma may be due to inherited predisposition. Many genes involved in familial cancers are frequently altered in the corresponding sporadic forms. We have investigated several genes known to be altered in sporadic gliomas for their potential contribution to familial glioma. Fifteen glioma patients with a family history of brain tumors were identified through the Mayo Clinic Department of Neurology (nine diffuse astrocytomas, two oligodendrogliomas, two mixed oligoastrocytomas, one pilocytic astrocytoma, and one pineal glioma). Eleven of the propositi had one or more first degree relative with a glioma. Lymphocyte DNA was derived from each of the patients and analyzed by polymerase chain reaction (PCR) and direct sequencing of the PTEN, p53, p16(INK4A)/p14(ARF), and CDK4 genes. In addition, fluorescence in situ hybridization (FISH) was performed on EBV-transformed lymphocytes from each affected individual to detect germline copy number of the p16(INK4A)/p14(ARF) tumor suppressor region. A p53 germline point mutation was identified in one family with some findings of Li-Fraumeni syndrome, and a hemizygous germline deletion of the p16(INK4A)/p14(ARF) tumor suppressor region was demonstrated by FISH in a family with history of both astrocytoma and melanoma. Thus, whereas germ-line mutations of PTEN, p53, p16(INK4A)/p14(ARF), and CDK4 are not common events in familial glioma, outside of familial cancer syndromes, point mutations of p53 and hemizygous deletions and other rearrangements of the p16(INK4A)/p14(ARF) tumor suppressor region may account for a subset of familial glioma cases. Collectively, these data lend genetic support to the heritable nature of some cases of glioma.
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PMID:Investigation of germline PTEN, p53, p16(INK4A)/p14(ARF), and CDK4 alterations in familial glioma. 1079 39

Normal human fibroblasts have been shown to undergo a p16(Ink4a)-associated senescence-like growth arrest in response to sustained activation of the Ras/Raf/MEK/ERK pathway. We noted a similar p16(Ink4a)-associated, senescence-like arrest in normal human astrocytes in response to expression of a conditional form of Raf-1. While HPV16 E7-mediated functional inactivation of the p16(Ink4a)/pRb pathway in astrocytes blocked the p16(Ink4a)-associated growth arrest in response to activation of Raf-1, it also revealed a second p21(Cip1)-associated, senescence-associated, beta-galactosidase-independent growth arrest pathway. Importantly, the p21(Cip1)-associated pathway was present not only in normal astrocytes but also in p53-, p14(ARF)-, and p16(Ink4a)/pRb-deficient high grade glioma cells that lacked the p16(Ink4a)-dependent arrest mechanism. These results suggest that normal human cells have redundant arrest pathways, which can be activated by Raf-1, and that even tumors that have dismantled p16(Ink4a)-dependent growth arrest pathways are potentially regulated by a second p21(Cip1)-dependent growth arrest pathway.
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PMID:Dual growth arrest pathways in astrocytes and astrocytic tumors in response to Raf-1 activation. 1127 20

Increased expression of focal adhesion kinase (FAK) was consistently observed in low- and high-grade astrocytomas and during glioblastoma progression after radiotherapy, but not in the more benign oligodendroglioma. In glioblastoma cell lines deficient for p53, p16(INK4A), and p14(ARF), FAK was inhibited in a dominant-negative manner by the focal adhesion targeting (FAT) domain, reducing invasion. In addition, caspase-3 activity was increased after serum withdrawal, or by cisplatin in the presence of serum, or upon loss of substrate attachment, and was in each case independent of PTEN status. Our results identify FAK as a potential target for anti-invasive strategies against infiltrating glioma cells.
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PMID:PTEN-independent induction of caspase-mediated cell death and reduced invasion by the focal adhesion targeting domain (FAT) in human astrocytic brain tumors which highly express focal adhesion kinase (FAK). 1147 98

Ink4a/Arf inactivation and epidermal growth factor receptor (EGFR) activation are signature lesions in high-grade gliomas. How these mutations mediate the biological features of these tumors is poorly understood. Here, we demonstrate that combined loss of p16(INK4a) and p19(ARF), but not of p53, p16(INK4a), or p19(ARF), enables astrocyte dedifferentiation in response to EGFR activation. Moreover, transduction of Ink4a/Arf(-/-) neural stem cells (NSCs) or astrocytes with constitutively active EGFR induces a common high-grade glioma phenotype. These findings identify NSCs and astrocytes as equally permissive compartments for gliomagenesis and provide evidence that p16(INK4a) and p19(ARF) synergize to maintain terminal astrocyte differentiation. These data support the view that dysregulation of specific genetic pathways, rather than cell-of-origin, dictates the emergence and phenotype of high-grade gliomas.
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PMID:Epidermal growth factor receptor and Ink4a/Arf: convergent mechanisms governing terminal differentiation and transformation along the neural stem cell to astrocyte axis. 1208 63

Deletion of the INK4a-ARF locus is found in the majority of human malignant gliomas. However, the role of INK4a-ARF loss in gliomagenesis is unclear. Animal modeling has shown that mice with targeted deletions in the Ink4a-Arf gene do not develop spontaneous gliomas. We have previously reported that combined KRas and Akt signaling could induce glioblastoma (GBM) formation from neural progenitor cells but had no effect in differentiated astrocytes. In this investigation, we have studied the effects of Ink4a-Arf loss on the formation of GBM induced by KRas and Akt gene transfer into neural progenitor cells and astrocytes. We show here that Ink4a-Arf deficiency allows for GBM formation from astrocytes and that it enhances tumor incidence in neural progenitor cells. Furthermore, KRas alone can cooperate with deletion of the Ink4a-Arf locus in tumor formation from both neural progenitor cells and astrocytes. The resulting tumors were nestin positive and resembled a spectrum of glioma morphologies ranging in astrocytic character depending on cell-of-origin and presence of activated Akt. Our data strongly supports the view that one role of loss of Ink4a-Arf in gliomagenesis could be to sensitize astrocytes to transformation through dedifferentiation in response to the appropriate oncogenic stimuli.
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PMID:Ink4a-Arf loss cooperates with KRas activation in astrocytes and neural progenitors to generate glioblastomas of various morphologies depending on activated Akt. 1235 67

Flavopiridol is a synthetic flavone, which inhibits growth in vitro and in vivo of several solid malignancies such as renal, prostate, and colon cancers. It is a potent cyclin-dependent kinase inhibitor presently in clinical trials. In this study, we examined the effect of flavopiridol on a panel of glioma cell lines having different genetic profiles: five of six have codeletion of p16(INK4a) and p14(ARF); three of six have p53 mutations; and one of six shows overexpression of mouse double minute-2 (MDM2) protein. Independent of retinoblastoma and p53 tumor suppressor pathway alterations, flavopiridol induced apoptosis in all cell lines but through a caspase-independent mechanism. No cleavage products for caspase 3 or its substrate poly(ADP-ribose) polymerase or caspase 8 were detected. The pan-caspase inhibitor Z-VAD-fmk did not inhibit flavopiridol-induced apoptosis. Mitochondrial damage measured by cytochrome c release and transmission electron microscopy was not observed in drug-treated glioma cells. In contrast, flavopiridol treatment induced translocation of apoptosis-inducing factor from the mitochondria to the nucleus. The proteins cyclin D(1) and MDM2 involved in the regulation of retinoblastoma and p53 activity, respectively, were down-regulated early after flavopiridol treatment. Given that MDM2 protein can confer oncogenic properties under certain circumstances, loss of MDM2 expression in tumor cells could promote increased chemosensitivity. After drug treatment, a low Bcl-2/Bax ratio was observed, a condition that may favor apoptosis. Taken together, the data indicate that flavopiridol has activity against glioma cell lines in vitro and should be considered for clinical development in the treatment of glioblastoma multiforme.
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PMID:Flavopiridol induces apoptosis in glioma cell lines independent of retinoblastoma and p53 tumor suppressor pathway alterations by a caspase-independent pathway. 1258 31

Human malignant gliomas arise from neural progenitor cells and/or dedifferentiated astrocytes. By now, they are genetically so well characterized that several murine glioma models have emerged that faithfully reiterate the typical histological features of the disease. In experimental animals, only one or two elements of the growth factor/Ras, PI3K/PTEN/PKB, p53/ARF/HDM2, and p16/Rb/cyclinD/CDK4 pathways are targeted. In human gliomas, many additional genes and pathways are targeted due to a most severe mutator phenotype that leads to the accumulation of countless epigenetic and genetic alterations. Changes that convey a growth advantage are selected for, leading to overgrowth of precursor cell populations with increasingly malignant tumor cell clones. While murine models represent a powerful tool for elucidating the role of genetic pathways, mechanisms of response and resistance to new therapeutic agents might be fundamentally different due to the high degree of genomic instability in the human disease. In fact, little is known about the molecular causes of genomic instability involved in gliomas, except for the rare Turcot's syndrome, O(6)-methylguanine-DNA methyltransferase, and the apurinic/apyrimidinic endonuclease Ape-1. Novel approaches that selectively exploit fundamental metabolic differences between tumor and normal cells have to consider these fundamental differences between human disease and presently available, highly sophisticated animal models.
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PMID:Genes and pathways driving glioblastomas in humans and murine disease models. 1278 72

Gliomas are tumors of the central nervous system with a wide spectrum of different tumor types. They range from pilocytic astrocytoma, with a generally good prognosis, to the extremely aggressive malignant glioblastoma. In addition to these 2 types of contrasting neoplasms, several other subtypes can be distinguished, each characterized by specific phenotypic, as well as genotypic features. Recently, the epigenotype, as evident from differentially methylated DNA loci, has been proposed to be useful as a further criterion to distinguish between tumor types. In our study, we screened 139 tissue samples, including 33 pilocytic astrocytomas, 46 astrocytomas of different grades, 7 oligoastrocytomas, 10 oligodendrogliomas, 10 glioblastoma multiforme samples and 33 control tissues, for methylation at CpG islands of 15 different gene loci. We used the semiquantitative high throughput method MethyLight to analyze a gene panel comprising ARF, CDKN2B, RB1, APC, CDH1, ESR1, GSTP1, TGFBR2, THBS1, TIMP3, PTGS2, CTNNB1, CALCA, MYOD1 and HIC1. Seven of these loci showed tumor specific methylation changes. We found tissue as well as grade specific methylation profiles. Interestingly, pilocytic astrocytomas showed no evidence of CpG island hypermethylation, but were significantly hypomethylated, relative to control tissues, at MYOD1. Our results show that glioma subtypes have characteristic methylation profiles and, with the exception of pilocytic astrocytomas, show both locus specific hyper- as well as hypomethylation.
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PMID:Distinct methylation profiles of glioma subtypes. 1279 56

BACKGROUND: The aim of this work was to investigate in vitro the putative role of EGR-1 in the growth of glioma cells. EGR-1 expression was examined during the early passages in vitro of 17 primary cell lines grown from 3 grade III and from 14 grade IV malignant astrocytoma explants. The explanted tumors were genetically characterized at the p53, MDM2 and INK4a/ARF loci, and fibronectin expression and growth characteristics were examined. A recombinant adenovirus overexpressing EGR-1 was tested in the primary cell lines. RESULTS: Low levels of EGR-1 protein were found in all primary cultures examined, with lower values present in grade IV tumors and in cultures carrying wild-type copies of p53 gene. The levels of EGR-1 protein were significantly correlated to the amount of intracellular fibronectin, but only in tumors carrying wild-type copies of the p53 gene (R = 0,78, p = 0.0082). Duplication time, plating efficiency, colony formation in agarose, and contact inhibition were also altered in the p53 mutated tumor cultures compared to those carrying wild-type p53. Growth arrest was achieved in both types of tumor within 1-2 weeks following infection with a recombinant adenovirus overexpressing EGR-1 but not with the control adenovirus. CONCLUSIONS: Suppression of EGR-1 is a common event in gliomas and in most cases this is achieved through down-regulation of gene expression. Expression of EGR-1 by recombinant adenovirus infection almost completely abolishes the growth of tumor cells in vitro, regardless of the mutational status of the p53 gene.
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PMID:Inhibition of cell growth by EGR-1 in human primary cultures from malignant glioma. 1471 80


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