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

Epidemiological studies of the association of variants p53 Arg72Pro and MDM2 single-nucleotide polymorphism 309 (SNP309) with glioma risk have produced inconsistent results. The aim of the current study was to evaluate the association of these 2 variants with glioma susceptibility using a meta-analysis approach. For p53 Arg72Pro, 10 case-control studies including 2587 glioma patients and 4061 unrelated controls were identified. The pooled odds ratios (ORs) for Arg/Pro heterozygotes and Pro/Pro homozygotes were 1.08 [95% confidence interval (95%CI) = 0.85-1.37] and 1.08 (95%CI = 0.85-1.36), respectively, when compared to Arg/Arg carriers. Under the dominant effect model, Pro allele carriers also showed no significantly elevated glioma risk (pooled OR = 1.11, 95%CI = 0.90-1.38), and similar results were found under the recessive-effect model (pooled OR = 1.17, 95%CI = 0.85-1.61). For variant MDM2 SNP309, 3 case-control studies including 606 cases and 309 controls were identified. A marginal association with glioma risk was found for heterozygous G/T carriers (pooled OR = 1.95, 95%CI = 1.00- 3.81), whereas homozygous G/G carriers showed an increased but not significantly elevated risk of glioma (pooled OR = 2.14, 95%CI = 0.71-6.45) compared with that of T/T homozygotes. We also found no significant association between the MDM2 SNP309 polymorphism and glioma risk (pooled OR = 1.86, 95%CI = 0.94-3.67 and pooled OR = 1.25, 95%CI = 0.62-2.56, respectively) under the dominant and recessive models. Taken together, the current data suggested that the 2 polymorphisms may not contribute to glioma susceptibility.
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PMID:Association of p53 Arg72Pro and MDM2 SNP309 polymorphisms with glioma. 2309 87

Glioblastoma multiforme (GBM) is the most common primary malignancy in the brain and confers a uniformly poor prognosis. Despite decades of research on the topic, limited progress has been made to improve the poor survival associated with this disease. GBM arises de novo (primary GBM) or via dedifferentiation of lower grade glioma (secondary GBM). While distinct mutations are predominant in each subtype, alterations of tumor suppressor p53 are the most common, seen in 25-30 % of primary GBM and 60-70 % of secondary GBM. Various roles of p53 that protect against neoplastic transformation include modulation of cell cycle, DNA repair, apoptosis, senescence, angiogenesis, and metabolism, resulting in an extremely complex signaling network. Mutations of p53 in GBM are most common in the DNA-binding domain, namely within six hotspot mutation sites (codons 175, 245, 248, 249, 273, and 282). These alterations generally result in loss-of-function, gain-of-function, and dominant-negative mutational effects for p53, however, the distinct effect of these mutation types in GBM pathogenesis remain unclear. Signaling alterations downstream from p53 (e.g., MDM2, MDM4, INK4/ARF), p53 isoforms (e.g., p63, p73), and microRNAs (e.g., miR-34) also play critical roles in modulating the p53 pathway. Despite novel mouse models of GBM showing that p53 combined with other mutation generate tumors de novo, the role of p53 as a molecular marker of GBM remains controversial with most studies failing to show an association with prognosis. Regarding treatment in GBM, p53 targeted-gene therapy and vaccinations have reached phase I clinical trials while therapeutic drugs are still in preclinical development. This review aims to discuss the most recent findings regarding the impact of p53 mutations on GBM pathogenesis, prognosis, and treatment.
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PMID:Current understanding of the role and targeting of tumor suppressor p53 in glioblastoma multiforme. 2373 87

The product of the MDMX (or MDM4) gene is structurally related to the MDM2 oncoprotein and is also capable of interacting with the tumor suppressor protein p53. The MDM4 gene is overexpressed in several human tumors, while its product can be detected as various isoforms. This study was aimed to find the presence of aberrant mRNA transcripts of MDM4 in human glioma and their association with the clinicopathological characteristics of glioma patients. 42 glioma tissues were examined for MDM4 mRNA splicing variants by RT-PCR. A total of four distinct transcript sizes (full length-MDM4 851 bp, MDM4-S 783 bp, MDM4-A 701 bp, MDM4-B 540 bp) were detected. In the present study, we first report the novel alternative splicing form of MDM4, MDM4-B (GenBank accession no.KC479043.1). Expression of MDM4-B was present in various stages of human gliomas, but no significant correlation between presence of MDM4-B and malignancy of glioma was observed. The expression level of MDM4-B mRNA detected by real-time PCR was not only significantly associated with tumor stages, but also with p53 mutation and Ki-67 status which are important clinical molecular markers of glioma. Our data indicate that the novel variant MDM4-B may play a role in glioma tumorigenesis or cancer progression.
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PMID:Identification and expression of a novel MDM4 splice variant in human glioma. 2399 48

PATZ1 is a transcriptional factor functioning either as an activator or a repressor of gene transcription depending upon the cellular context. It appears to have a dual oncogenic/anti-oncogenic activity. Indeed, it is overexpressed in colon carcinomas, and its silencing inhibits colon cancer cell proliferation or increases sensitivity to apoptotic stimuli of glioma cells, suggesting an oncogenic role. Conversely, the development of B-cell lymphomas, sarcomas, hepatocellular carcinomas and lung adenomas in Patz1-knockout (ko) mice supports its tumour suppressor function. PATZ1 role in mouse lymphomagenesis is mainly because of the involvement of PATZ1 in BCL6-negative autoregulation. However, this does not exclude that PATZ1 may be involved in tumorigenesis by other mechanisms. Here, we report that PATZ1 interacts with the tumour suppressor p53 and binds p53-dependent gene promoters, including those of BAX, CDKN1A and MDM2. Knockdown of PATZ1 in HEK293 cells reduces promoter activity of these genes and inhibits their expression, suggesting a role of PATZ in enhancing p53 transcriptional activity. Consistently, Patz1-ko mouse embryonic fibroblasts (MEFs) show decreased expression of Bax, Cdkn1a and Mdm2 compared with wild-type (wt) MEFs. Moreover, Patz1-ko MEFs show a decreased percentage of apoptotic cells, either spontaneous or induced by treatment with 5-fluorouracil (5FU), compared with wt controls, suggesting a pro-apoptotic role for PATZ1 in these cells. However, PATZ1 binds p53-target genes also independently from p53, exerting, in the absence of p53, an opposite function on their expression. Indeed, knockdown of PATZ1 in p53-null osteosarcoma cells upregulates BAX expression and decreases survival of 5FU-treated cells, then suggesting an anti-apoptotic role of PATZ1 in p53-null cancer cells. Therefore, these data support a PATZ1 tumour-suppressive function based on its ability to enhance p53-dependent transcription and apoptosis. Conversely, its opposite and anti-apoptotic role in p53-null cancer cells provides the perspective of PATZ1 silencing as a possible adjuvant in the treatment of p53-null cancer.
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PMID:PATZ1 interacts with p53 and regulates expression of p53-target genes enhancing apoptosis or cell survival based on the cellular context. 2433 83

G19 is a novel homogeneous sulfated oligosaccharide, prepared from Grateloupia filicina. In the present study, we first reported that oligosaccharide G19 exhibited a dose- and time-dependent anti-proliferation effect against U-87 malignant gliomas (MG) human glioma cells. Further studies indicated that G19 strongly bound to epidermal growth factor (EGF), suppressed EGF receptor phosphorylation and interrupted the phosphatidylinositol-3 kinase/Akt pathway in the cancer cells. Moreover, G19 elevated intracellular reactive oxygen species levels and caused endogenous DNA damage. These actions were associated with activation of ataxia-telangiectasia-mutated/checkpoint kinase 2 pathway. The downregulation of MDM2 with stabilizing p53 and the nuclear location of p21 were induced by G19 to cause cell cycle arrest and apoptosis to some extent. Meanwhile, intrinsic mitochondrial pathway and extrinsic death receptor pathway were involved in G19-mediated apoptosis. Pretreatment with free radical scavenger N-acetyl-l-cysteine nearly completely inversed G19-induced cell growth inhibition, cell cycle arrest and apoptosis in U-87 MG cells. Importantly, G19 could inhibit the growth of U-87 MG tumor cells xenograft in nude mice. The results suggested that G19 could be served as a new targeting drug candidate for human glioma treatment.
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PMID:Oligosaccharide G19 inhibits U-87 MG human glioma cells growth in vitro and in vivo by targeting epidermal growth factor (EGF) and activating p53/p21 signaling. 2479 78

Chalcones are important compounds that exhibit multiple biological activities, including anti-inflammatory, antimitotic and antibacterial properties. In the present study, we have analyzed the potential anti-cancer activity of a chalcone named N9 (a hybrid chalcone-quinoxaline compound) using in vitro and in vivo experimental glioma models. Here, we report N9-induced inhibition of cell proliferation and also N9-induced cell death in a concentration-dependent manner in U87-MG glioma cells. These effects of N9 appear to be associated with its ability to inhibit the expression of cell cycle-associated proteins, and also the augmentation in the expression of the p21 (p21/Cip1) protein, a cyclin-dependent kinase inhibitor. Additionally, N9 also potentiates the production of the pro-apoptotic markers Bax and p53 via inhibition of MDM2. Moreover, our results show that N9 also significantly enhanced apoptosis of U87-MG cells with disruption of mitochondrial membrane potential, generation of ROS and caspase-9 activation. In vivo experiments carried out in a murine xenograft model of U87-MG revealed that N9 produced a significant reduction of tumors volume when compared to vehicle treated mice. Collectively, data demonstrate that N9 possess in vitro and in vivo anti-cancer activity, an effect that seems to involve the induction of p53 and p21 proteins, as well as, the activation of mitochondrial apoptosis pathway associated with the inhibition of protein MDM2. Overall, this study suggests N9 is affecting a variety of intracellular pathways related to tumor apoptosis. Perhaps N9 or derivate molecules could represent new potential drugs for cancer therapeutics.
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PMID:In vitro and in vivo anti-glioma activity of a chalcone-quinoxaline hybrid. 2546 14

Mechanistic target of rapamycin (mTOR) is a master regulator of cell growth through its ability to stimulate ribosome biogenesis and mRNA translation. In contrast, the p53 tumor suppressor negatively controls cell growth and is activated by a wide range of insults to the cell. The mTOR and p53 signaling pathways are connected by a number of different mechanisms. Chemotherapeutics that inhibit ribosome biogenesis often induce nucleolar stress and activation of p53. Here we have investigated how the p53 response to nucleolar stress is affected by simultaneous mTOR inhibition in osteosarcoma and glioma cell lines. We found that inhibitors of the mTOR pathway including rapamycin, wortmannin, and caffeine blunted the p53 response to nucleolar stress induced by actinomycin D. Synthetic inhibitors of mTOR (temsirolimus, LY294.002 and PP242) also impaired actinomycin D triggered p53 stabilization and induction of p21. Ribosomal protein (RPL11) is known to be required for p53 protein stabilization following nucleolar stress. Treatment of cells with mTOR inhibitors may lead to reduced synthesis of RPL11 and thereby destabilize p53. We found that rapamycin mimicked the effect of RPL11 depletion in terms of blunting the p53 response to nucleolar stress. However, the extent to which the levels of p53 and RPL11 were reduced by rapamycin varied between cell lines. Additional mechanisms whereby rapamycin blunts the p53 response to nucleolar stress are likely to be involved. Indeed, rapamycin increased the levels of endogenous MDM2 despite inhibition of its phosphorylation at Ser-166. Our findings may have implications for the design of combinatorial cancer treatments with mTOR pathway inhibitors.
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PMID:mTOR inhibitors blunt the p53 response to nucleolar stress by regulating RPL11 and MDM2 levels. 2548 47

Endoplasmic reticulum stress and hypoxia are necessary components of malignant tumors growth and suppression of ERN1 (from endoplasmic reticulum to nuclei-1) signalling pathway, which is linked to the apoptosis and cell death processes, significantly decreases proliferative processes. Glioma cells with ERN1 knockdown were used in order to investigate the effect of ERNI blockade on the expression of TP53, MDM2, PERP, and USP7 genes and its hypoxic regulation. We have studied the expression of TP53 (tumor protein 53), MDM2 (TP53 E3 ubiquitin protein ligase homolog), PERP (TP53 apoptosis effector), and USP7 (ubiquitin specific peptidase 7) genes, which are related to cell proliferation and apoptosis, in glioma cells with ERN1 knockdown under hypoxic condition. It was shown that blockade of ERNI gene function in U87 glioma cells intensified the expression of TP53 and USP7 genes, but decreased the expression ofMDM2 and PERP genes. Thus, an enhanced expression of TP53 gene in ERN1 knockdown glioma cells correlates with the decreased level of ubiquitin ligase MDM2 and increased expression level of USP7 which deubiquitinates TP53 and MDM2 and induces TP53-dependent cell growth repression and apoptosis. At the same time, the expression levels of TP53, MDM2, and USP7 genes do not change significantly in glioma cells with suppression of endoribonuclease activity only, but PERP gene expression is strongly increased. Moreover, the expression of TP53 and UPS7 genes is decreased in hypoxic conditions in control glioma cells only; however, MDM2 and PERP gene expressions are increased in both cell types, being more significant in ERN1 knockdown cells. Thus, the expression of genes encoding TP53 and related to TP53 factors depends upon the endoplasmic reticulum stress signaling as well as on hypoxia, and correlates with suppression of glioma growth under ERN1 knockdown.
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PMID:ERN1 knockdown modifies the hypoxic regulation of TP53, MDM2, USP7 and PERP gene expressions in U87 glioma cells. 2550 87

CD24 is overexpressed in nearly 70% human cancers, whereas TP53 is the most frequently mutated tumour-suppressor gene that functions in a context-dependent manner. Here we show that both targeted mutation and short hairpin RNA (shRNA) silencing of CD24 retard the growth, progression and metastasis of prostate cancer. CD24 competitively inhibits ARF binding to NPM, resulting in decreased ARF, increase MDM2 and decrease levels of p53 and the p53 target p21/CDKN1A. CD24 silencing prevents functional inactivation of p53 by both somatic mutation and viral oncogenes, including the SV40 large T antigen and human papilloma virus 16 E6-antigen. In support of the functional interaction between CD24 and p53, in silico analyses reveal that TP53 mutates at a higher rate among glioma and prostate cancer samples with higher CD24 mRNA levels. These data provide a general mechanism for functional inactivation of ARF and reveal an important cellular context for genetic and viral inactivation of TP53.
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PMID:Intracellular CD24 disrupts the ARF-NPM interaction and enables mutational and viral oncogene-mediated p53 inactivation. 2560 May 90

CDK4 inhibitors (CDK4i) earned Breakthrough Therapy Designation from the FDA last year and are entering phase III clinical trials in several cancers. However, not all tumors respond favorably to these drugs. CDK4 activity is critical for progression through G1 phase and into the mitotic cell cycle. Inhibiting this kinase induces Rb-positive cells to exit the cell cycle into either a quiescent or senescent state. In this report, using well-differentiated and dedifferentiated liposarcoma (WD/DDLS) cell lines, we show that the proteolytic turnover of MDM2 is required for CDK4i-induced senescence. Failure to reduce MDM2 does not prevent CDK4i-induced withdrawal from the cell cycle but the cells remain in a reversible quiescent state. Reducing MDM2 in these cells drives them into the more stable senescent state. CDK4i-induced senescence associated with loss of MDM2 is also observed in some breast cancer, lung cancer and glioma cell lines indicating that this is not limited to WD/DDLS cells in which MDM2 is overexpressed or in cells that contain wild type p53. MDM2 turnover depends on its E3 ligase activity and expression of ATRX. Interestingly, in seven patients the changes in MDM2 expression were correlated with outcome. These insights identify MDM2 and ATRX as new regulators controlling geroconversion, the process by which quiescent cells become senescent, and this insight may be exploited to improve the activity of CDK4i in cancer therapy.
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PMID:MDM2 turnover and expression of ATRX determine the choice between quiescence and senescence in response to CDK4 inhibition. 2580 70


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