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 have previously shown that heat shock induces p53-dependent WAF1 expression. To understand the role of protein kinases in the heat-induced p53-mediated signal transduction pathway, the effects of H-7, a serine/threonine kinase inhibitor, on WAF1 accumulation were investigated using two human glioblastoma cell lines differing in p53 status or their transfectants with various p53-expression vectors. Unexpectedly, H-7 alone induced p53-dependent WAF1 accumulation with a biphasic pattern depending on H-7 dose; i.e., low doses of H-7 induced the accumulation of both p53 and WAF1, whereas, a high dose of H-7 induced p53 but no WAF1 accumulation, suggesting that p53 accumulation and p53-dependent WAF1 expression are separable. Heat shock and H-7 induce p53-dependent WAF1 accumulation through different pathways as shown in A-172 cells stably expressing a temperature-sensitive mutant p53. However, our results show that these two pathways cross-talk with each other in the combined treatment of H-7 and heat shock studies. These findings indicate that inhibition of protein kinases can act as a novel stress to evoke the p53 pathway and that p53 activation by heat shock requires activation of yet unidentified protein kinases in vivo. The cross-talks between H-7 and heat shock in the p53 pathway provide the first evidence for the complex interactions between different stress signaling pathways in the modulation of p53 in vivo.
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PMID:Bifunctional effects of a protein kinase inhibitor (H-7) on heat-induced p53-dependent WAF1 accumulation. 941 81

The aim of this study was to demonstrate that the induction of growth arrest in human glioblastoma multiforme (GBM) cell lines by retrovirus-mediated transduction of growth control genes was dependent upon the integrity of specific endogenous control pathways. We assessed the status of the endogenous p16INK4A, p21CIP1, pRb, or p53 genes in eight GBM lines. As expected, we found varied combinations of gene defects. The outcome of transducing five of these cell lines with p16INK4A, p21CIP1, pRb, or p53 genes was not entirely predictable. The growth-inhibitory effects mediated by the transfer of the gene encoding p16 was dependent on the presence of the pRb protein, but was independent of p53 status. p21, a broadly active CDK inhibitor and a strong inducer of growth arrest, was not a universal growth suppressor in the group of glioblastoma cell lines analyzed. The suppression of GBM cell proliferation by viruses encoding pRb or p53 was generally predictable and appeared to be independent of the status of either p16 or p21. Suppression of cell growth was assessed by a colony formation assay, by observance of alterations in morphology, and by cell viability staining for trypan blue exclusion. Our findings suggest that to accomplish the suppression of GBM cell proliferation by the transduction of these cell-cycle control genes, the status of endogenous cell-cycle control genes must be taken into account.
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PMID:Restoration of growth arrest by p16INK4, p21WAF1, pRB, and p53 is dependent on the integrity of the endogenous cell-cycle control pathways in human glioblastoma cell lines. 945 56

Little is known about the relationship between genetic recombination mechanisms and loss of tumour suppressor genes in solid tumours. Here, we demonstrate deletion and truncation of both p53 alleles in a primary human glioblastoma and a derived cell line as the combined result of a t(17;20) reciprocal translocation and a 1.1 Mbp genomic deletion on chromosome 17p, starting in intron 4 of the p53 gene and ending at the telomeric CA-repeat marker D17S960. These results (i) suggest that genetic instability can lead to loss of tumour suppressor gene function in solid cancers, (ii) provide mapping of one such recombination event at the nucleotide level, and (iii) establish the orientation of the p53 gene on chromosome 17 as: centromere 5'-3'-telomere.
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PMID:Genetic instability leads to loss of both p53 alleles in a human glioblastoma. 946 57

To examine whether protein kinase C (PKC) contributes to p53-dependent WAF1 induction after heat treatment, the effects of calphostin C (CAL), a specific inhibitor of PKC, on WAF1 induction were analyzed by PKC activity and gel mobility-shift assays and Western blot analysis in human glioblastoma cell lines. Heat-induced accumulation of WAF1 in A-172 cells carrying wild-type p53 (wtp53) was suppressed by CAL in a dose-dependent manner. In T98G cells carrying mutant p53 (mp53), no significant accumulation of WAF1 was observed after heat treatment and CAL exerted no significant effects on this response of T98G cells. In accordance with the accumulation of WAF1, heat-induced activation of the binding ability of p53 to p53 consensus sequence (p53 CON) was suppressed by CAL in A-172 cells but no DNA-binding activity was observed in the mp53 in T98G cells. PKC in A-172 cells was activated rapidly (within 5 min) after heat treatment in the membrane fraction but not in the cytosolic fraction. When the cell lines were treated with the PKC activator, 12-O-tetradecanoyl-phorbol-13-acetate (TPA), WAF1 was accumulated in A-172 cells in a dose-dependent manner but not in T98G cells. In addition, the cellular contents of WAF1 after heating did not increase in A-172 cells transformed with mp53. These results suggest that PKC contributes to heat-induced signal transduction leading to p53-dependent WAF1 induction in a way that PKC is involved in the specific DNA-binding activation of p53.
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PMID:Contribution of protein kinase C to p53-dependent WAF1 induction pathway after heat treatment in human glioblastoma cell lines. 947 48

A large number of oncogenes have been identified as aberrant in gliomas, but only the erbB oncogene (gene encoding the epidermal growth factor receptor [EGFR]) is amplified in an appreciable number. The loss or mutation of tumor-suppressor genes located on different autosomes may be associated with progression of malignant gliomas. The p53 tumor-suppressor gene (located on chromosome 17) is frequently associated with the loss of one allele in malignant gliomas, although a large number of malignant gliomas have no p53 mutations. Some of the latter tumors have an amplified murine double minute 2 (MDM2) gene, which suppresses p53 gene activity. Genetic material from chromosome 10 may also be lost, especially in glioblastoma multiforme. In addition to the aberrant expression of EGFR, another growth factor, platelet-derived growth factor, or PDGF (ligand and/or receptors) can be overexpressed, giving cells a selective growth advantage. The blood-brain barrier is substantially altered in malignant gliomas, resulting in cerebral edema. Therapy for malignant gliomas includes surgery, radiation therapy, and chemotherapy. Surgical resection that leaves little residual tumor produces longer survival than less vigorous surgery. Radiation therapy to a dose of at least 60 Gy is required to treat malignant gliomas. Increased survival beyond that produced by standard external radiotherapy requires much larger doses; interstitial radiotherapy permits such dosing. Radiosurgery is being tested. Chemotherapy with nitrosoureas is modestly useful but appears to benefit patients with anaplastic astrocytoma more so than those with glioblastoma.
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PMID:Biology and treatment of malignant glioma. 950 24

Induction of WAF1 expression was investigated in human glioblastoma cell lines differing in p53 gene statuses after cold shock treatment. Accumulation of both wild-type (wt) and mutant p53 (mp53) was induced by cold shock at 4 degrees C for 60 min, however, WAF1 accumulation was induced by cold shock in A-172 cells carrying the wtp53 but not in T98G cells carrying the mp53. Inactivation of wtp53 by a dominant negative p53 mutant (p53Trp248) abolished cold shock-induced WAF1 expression in A-172 transfectant cells. Furthermore, no WAF1 expression was induced by cold shock in p53-deficient human osteosarcoma Saos-2 cells. Northern blot analysis showed that the WAF1 but not p53 gene was activated by cold shock only in A-172 cells. These findings suggest that WAF1 expression is cold shock-inducible in human glioblastoma cells, and that this induction may be due to signal transduction mediated by p53 in response to non-genotoxic stress, cold shock.
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PMID:p53-dependent induction of WAF1 by cold shock in human glioblastoma cells. 952 49

Astrocytomas are the most common tumors of the central nervous system (CNS). Their malignant counterparts, anaplastic astrocytoma and glioblastoma, are lethal neoplasms with poor clinical outcome and they frequently carry mutations of TP53 tumor suppressor gene. In order to determine the frequency and type of this molecular alteration in the Polish population, we analyzed the polymerase chain reaction products corresponding to the most conservative exons 5-8 for single-strand conformation polymorphism and confirmed the presence of mutations by direct DNA sequencing. We identified mutations in one of five (20%) anaplastic astrocytomas and in eight of 28 (29%) glioblastomas; the mutations were most frequently identified in the exon 8 (six glioblastomas). The frequency of TP53 mutations is thus similar to the corresponding data from other studies, and the type of mutations suggests the participation of endogenous etiological factor.
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PMID:TP53 mutations in malignant astrocytomas. 952 27

We have identified two novel human genes homologous to BAI1 (brain-specific angiogenesis inhibitor 1), an angiogenesis inhibitor that is a candidate for involvement in development of glioblastoma. Like BAI1, these two genes, designated BAI2 and BAI3, were specifically expressed in brain, and are likely to be expressed in the same type of cells. However, in spite of similar tissue specificity among the three BAI genes, only BAI1 is transcriptionally regulated by p53. BAI3 expression was absent in two of nine glioblastoma cell lines examined and was significantly reduced in three of the remaining seven. These data suggest that members of this novel gene family may play important roles in suppression of glioblastoma. BAI1, BAI2 and BAI3 were mapped to 8q24, 1p35 and 6q12, respectively.
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PMID:Cloning and characterization of BAI2 and BAI3, novel genes homologous to brain-specific angiogenesis inhibitor 1 (BAI1). 953 23

The induction of WAF1 gene expression after the treatment with the anticancer agent 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU; nimustine hydrochloride) was studied in two human glioblastoma cell lines: U-87MG, which bears the wild-type p53 gene, and T98G, which bears the mutant p53 gene. A marked accumulation of WAF1 was observed 3 h after ACNU treatment in both cell lines. The induction of WAF1 mRNA by ACNU was detected by northern blot analysis in these cells. Binding activity of p53 to a p53 consensus sequence increased after treatment in U-87MG cells but not in T98G cells. The existence of a p53-independent WAF1 induction pathway was supported by the apparent accumulation of WAF1 after ACNU treatment in the p53-null human osteosarcoma cell line Saos-2. These findings suggest that there are two possible pathways for WAF1 induction: the p53-dependent pathway through the p53-responsive element and the p53-independent pathway through other elements.
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PMID:p53-independent WAF1 induction by ACNU in human glioblastoma cells. 953 48

Glioblastomas may develop rapidly without clinical and histopathological evidence of a less malignant precursor lesion (de novo or primary glioblastoma) or through progression from low-grade or anaplastic astrocytoma (secondary glioblastoma). Primary glioblastomas typically show overexpression of EGFR, but rarely p53 mutations, while secondary glioblastomas frequently carry a p53 mutation, but usually lack overexpression of EGFR, suggesting that these glioblastoma subtypes develop through distinct genetic pathways. In the present study, we assessed the expression of Fas/APO-1 (CD95), an apoptosis-mediating cell membrane protein, and its relation to necrosis phenotype in primary and secondary glioblastomas. Large areas of ischemic necroses were observed in all 18 primary glioblastomas, but were significantly less frequent in secondary glioblastomas (10 of 19, 53%; p = 0.0004). Fas expression was predominantly observed in glioma cells surrounding large areas of necrosis and was thus significantly more frequent in primary glioblastomas (18 of 18, 100%) than in secondary glioblastomas (4 of 19, 21%; p < 0.0001), suggesting that these clinically and genetically defined subtypes of glioblastoma differ in the extent and mechanism of necrogenesis. Necrosis and microvascular proliferation are histologic hallmarks of the glioblastoma. Following incubation of glioblastoma cell lines under hypoxic/anoxic conditions for 24-48 hours, Fas mRNA levels remained unchanged, whereas VEGF expression was markedly upregulated. This suggests that in contrast to VEGF Fas expression is not induced by ischemia/hypoxia. Analysis of Fas mRNA levels in a glioblastoma cell line containing a p53 mutation and an inducible wild-type p53 gene showed little difference under induced and noninduced conditions, suggesting that in glioblastomas, Fas expression is not directly linked to the p53 status.
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PMID:Necrogenesis and Fas/APO-1 (CD95) expression in primary (de novo) and secondary glioblastomas. 960 Feb 16


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