Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Loss of heterozygosity for sequences located on chromosome 17p in several tumor types is often associated with mutations in the tumor suppressor gene p53. We previously showed consistent deletion of chromosome 17p12-13.1 in medulloblastoma, a common childhood brain tumor. Using denaturing gradient gel electrophoresis and direct sequencing, we have detected p53 mutations in only two of 20 medulloblastoma specimens. Moreover, additional RFLP studies of these 20 specimens showed loss of heterozygosity at a more distal and distinct site, 17p13.3. Deletion of 17p almost invariably signified a negative prognosis. Our results suggest that p53 mutations may contribute to the pathogenesis of medulloblastoma in relatively few cases. The consistent deletion of other discrete loci on 17p suggests that additional or alternative tumor suppressor genes may contribute to the tumor's phenotype.
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PMID:Involvement of multiple chromosome 17p loci in medulloblastoma tumorigenesis. 134 96

Cytogenetic and molecular analyses of primitive neuroectodermal tumors (PNETs) of the central nervous system (CNS) have demonstrated material losses of 17p, the region that contains the TP53 gene, as the most frequent abnormality. Mutations in the TP53 gene are, however, very rare in these tumors. These findings strongly suggest that another, as yet unidentified, gene on 17p may be involved. We performed a search for loss of heterozygosity (LOH) on 17p by microsatellite markers on 26 childhood CNS tumors as well as TP53 gene mutations (exons 5-8) by single-strand conformational polymorphism analysis on 41 pediatric brain tumor samples of distinct histologic types. LOH was detected in 10 cases: 7 PNET, 2 astrocytomas, and 1 glioblastoma multiforme. In 4 of the PNETs the losses were limited to more distal markers. On the other hand, TP53 mutations were detected in 6 of 41 samples studied. Our results not only confirm the low penetrance of the TP53 gene on pediatric CNS tumors, but also provide further evidence of a putative tumor suppressor gene distal to TP53, between markers (D17S938, D17S926) and 17pter, specifically taking part in the development of PNET.
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PMID:Pediatric brain tumors: loss of heterozygosity at 17p and TP53 gene mutations. 954 59

Brain malignancies represent the most common solid tumors in children, and they are responsible for significant mortality and morbidity. The molecular basis of the most common malignant pediatric brain tumor, medulloblastoma, is poorly understood. Mutations in several genes including the human homologue of the Drosophila segment polarity gene, patched (PTCH), the adenomatous polyposis coli gene (APC), beta-catenin, and p53 have been reported in subsets of hereditary and sporadic medulloblastoma. Inactivation of one Ptc allele in mice results in a 14% incidence of medulloblastoma. Here, we report a dramatic increase in the incidence (>95%) and accelerated development (prior to 12 weeks of age) of medulloblastoma in mice heterozygous for Ptc that lack p53. The acceleration of tumorigenesis in Ptc+/- mice is specific for loss of p53, because no change in tumor incidence was observed in Ptc+/- mice carrying a mutation in APC (Min+/-) or in Ptc+/- mice deficient in p19ARF. Thus, there is a specific interaction between p53 loss and heterozygosity of Ptc that results in medulloblastoma. This may be a consequence of increased genomic instability associated with loss of p53 function that may enhance the rate of acquisition of secondary mutations. Ptc+/- p53-/- mice provide a useful model for investigation of the molecular bases of medulloblastoma and for evaluation of the efficacy of therapeutic intervention strategies in a spontaneously arising endogenous brain tumor.
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PMID:Loss of p53 but not ARF accelerates medulloblastoma in mice heterozygous for patched. 1121 43

Amplification of the EGFR, mdm2, CDK4 and PDGFR A genes has been widely demonstrated in adult malignant gliomas, almost exclusively glioblastomas. To determine the role of these mutational events in pediatric astrocytic gliomas we investigated the presence of EGFR, mdm2, CDK4 and PDGFR A gene amplification in 38 childhood brain tumor biopsies, including 24 low-grade astrocytomas and 14 malignant tumors. We used differential PCR assay on DNA extracted either from paraffin embedded or frozen tissues. EGFR gene amplification was detected in 4 out of 14 malignant tumors; no low-grade astrocytoma showed amplification. Tumors with EGFR gene amplification were negative for the presence of p53 mutations, as observed in a previous study. One glioblastoma showed PDGFR A amplification, while no amplifications were observed for mdm2 and CDK4 genes. These data are in line with those obtained from studies on gliomas of adults and suggest the existence of two different subsets of malignant gliomas also in pediatric brain tumors: one carrying EGFR gene amplification, the other showing p53 mutations.
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PMID:Molecular genetic changes in a series of neuroepithelial tumors of childhood. 1224 Nov 4

Medulloblastoma is the most common malignant pediatric brain tumor. In mice, Ptc1 haploinsufficiency and disruption of DNA repair (DNA ligase IV inactivation) or cell cycle regulation (Kip1, Ink4d, or Ink4c inactivation), in conjunction with p53 dysfunction, predispose to medulloblastoma. To identify genes important for this tumor, we evaluated gene expression profiles in medulloblastomas from these mice. Unexpectedly, medulloblastoma expression profiles were very similar among tumors and also to those of developing cerebellum. However, 21 genes were specifically up-regulated in medulloblastoma, including sFrp1, Ptc2, and Math1, members of signaling pathways that regulate cerebellar development. Coordinated deregulation of these same genes also occurred in a large subset of human medulloblastomas. These data identify a group of genes that is central to medulloblastoma tumorigenesis.
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PMID:A molecular fingerprint for medulloblastoma. 1450 Mar 78

Medulloblastoma (MB) is the most common malignant pediatric brain tumor which is thought to originate from cerebellar granule cell precursors (CGNPs) that fail to properly exit the cell cycle and differentiate. Although mutations in the Sonic Hedgehog (Shh) signaling pathway occur in 30% of cases, genetic alterations that account for MB formation in most patients have not yet been identified. We recently determined that the cyclin D-dependent kinase inhibitor, p18(Ink4c), is expressed as CGNPs exit the cell cycle, suggesting that this protein might play a central role in arresting the proliferation of these cells and in timing their subsequent migration and differentiation. In mice, disruption of Ink4c collaborates independently with loss of p53 or with inactivation of the gene (Ptc1) encoding the Shh receptor, Patched, to induce MB formation. Whereas loss of both Ink4c alleles is required for MB formation in a p53-null background, Ink4c is haplo-insufficient for tumor suppression in a Ptc(1+/-) background. Moreover, MBs derived from Ptc(1+/-) mice that lack one or two Ink4c alleles retain wild-type p53. Methylation of the INK4C (CDKN2C) promoter and complete loss of p18(INK4C) protein expression were detected in a significant fraction of human MBs again pointing toward a role for INK4C in suppression of MB formation.
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PMID:The CDK inhibitor p18Ink4c is a tumor suppressor in medulloblastoma. 1647 72

Originally identified as factors affecting Drosophila embryogenesis, the Hedgehog (Hh) pathway is one of the primary signaling systems that specify patterns of cell growth and differentiation during vertebrate development. Mutations in various components of this pathway frequently occur in tumors originated from the skin, cerebellum, and skeletal muscle, and abnormal pathway activity is associated with a subset of lung, digestive tract, pancreatic, and prostate cancers. Because of these potent biological activities, this pathway is negatively regulated at multiple levels to ensure appropriate signaling responses. Suppressor of fused (Sufu) is one such negative regulator of Hh signaling. Although not essential in Drosophila, Sufu is absolutely required for mouse embryonic development. Mutations of Sufu are associated with a childhood brain tumor in human and an increased susceptibility to the same type of cancer in the TP53 null background in mice, and RNAi-mediated silencing of Sufu is sufficient to activate the Hh signaling in cultured fibroblasts. All these data point to a central role of Sufu in controlling the vertebrate Hh signaling pathway; however, for years what exactly Sufu does in the Hh pathway and what controls its activity remains a deep mystery. This chapter will go over all studies curated in the PubMed database with Sufu as a main subject during the past 17 years, and attempt to provide a balanced view on Sufu gene and protein structure, activities in Drosophila as well as mammalian development, and its involvement in cancer.
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PMID:Role and regulation of human tumor suppressor SUFU in Hedgehog signaling. 1905 41

Pilocytic astrocytoma (PA) is the most common pediatric brain tumor. Most arise in the cerebellum, but they also can develop in the brainstem and optic nerve, where gross total resection (GTR) is not possible. In the absence of GTR, significant variability in both clinical behavior and histology exists. To identify potential markers associated with poor clinical outcome, we retrospectively assessed pathological features in 107 patients with PAs. We identified four pathological features (necrosis, oligodendroglioma-like features, vascular hyalinization, and calcification) that showed a significant correlation with decreased event-free survival (EFS). Similar to previous reports, we also found that PAs involving the optic pathway were associated with worse EFS compared with those arising in other locations. In contrast, mitotic index, p53 immunoreactivity and hyperactivation of several mitogenic signaling pathways (MAPK, CREB, mTOR) did not demonstrate a statistically significant relationship with EFS. Lastly, we did find a statistical trend between EFS and the number of CD68+ cells, suggesting that non-neoplastic elements of the tumor microenvironment may influence subsequent growth and clinical recurrence. Collectively, the identification of specific histopathologic features associated with clinical outcome may improve our ability to determine which PAs are more likely to exhibit clinical progression and require more vigilant observation.
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PMID:Histopathologic predictors of pilocytic astrocytoma event-free survival. 1927 Dec 26

Disruption of cerebellar granular neuronal precursor (GNP) maturation can result in defects in motor coordination and learning, or in medulloblastoma, the most common childhood brain tumor. The Sonic Hedgehog (Shh) pathway is important for GNP proliferation; however, the factors regulating the extent and timing of GNP proliferation, as well as GNP differentiation and migration are poorly understood. The p53 tumor suppressor has been shown to negatively regulate the activity of the Shh effector, Gli1, in neural stem cells; however, the contribution of p53 to the regulation of Shh signaling in GNPs during cerebellar development has not been determined. Here, we exploited a hypomorphic allele of Mdm2 (Mdm2(puro)), which encodes a critical negative regulator of p53, to alter the level of wild-type MDM2 and p53 in vivo. We report that mice with reduced levels of MDM2 and increased levels of p53 have small cerebella with shortened folia, reminiscent of deficient Shh signaling. Indeed, Shh signaling in Mdm2-deficient GNPs is attenuated, concomitant with decreased expression of the Shh transducers, Gli1 and Gli2. We also find that Shh stimulation of GNPs promotes MDM2 accumulation and enhances phosphorylation at serine 166, a modification known to increase MDM2-p53 binding. Significantly, loss of MDM2 in Ptch1(+/-) mice, a model for Shh-mediated human medulloblastoma, impedes cerebellar tumorigenesis. Together, these results place MDM2 at a major nexus between the p53 and Shh signaling pathways in GNPs, with key roles in cerebellar development, GNP survival, cerebellar foliation, and MB tumorigenesis.
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PMID:The p53 inhibitor MDM2 facilitates Sonic Hedgehog-mediated tumorigenesis and influences cerebellar foliation. 2143 45

Medulloblastoma is the most common malignant childhood brain tumor. The protein phosphatase and oncogene WIP1 is over-expressed or amplified in a significant number of primary human medulloblastomas and cell lines. In the present study, we examine an important mechanism by which WIP1 promotes medulloblastoma growth using in vitro and in vivo models. Human cell lines and intracerebellar xenografted animal models were used to study the role of WIP1 and the major TP53 regulator, HDM2, in medulloblastoma growth. Stable expression of WIP1 enhances growth of TP53 wild-type medulloblastoma cells, compared with cells with stable expression of an empty-vector or mutant WIP1. In an animal model, WIP1 enhances proliferation and reduces the survival of immunodeficient mice bearing intracerebellar xenografted human medulloblastoma cells. Cells with increased WIP1 expression also exhibit increased expression of HDM2. HDM2 knockdown or treatment with the HDM2 inhibitor Nutlin-3a, the active enantomer of Nutlin-3, specifically inhibits the growth of medulloblastoma cells with increased WIP1 expression. Nutlin-3a does not affect growth of medulloblastoma cells with stable expression of an empty vector or of mutant WIP1. Knockdown of WIP1 or treatment with the WIP1 inhibitor CCT007093 results in increased phosphorylation of known WIP1 targets, reduced HDM2 expression, and reduced growth specifically in WIP1 wild-type and high-expressing medulloblastoma cells. Combined WIP1 and HDM2 inhibition is more effective than WIP1 inhibition alone in blocking growth of WIP1 high-expressing medulloblastoma cells. Our preclinical study supports a role for therapies that target WIP1 and HDM2 in the treatment of medulloblastoma.
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PMID:HDM2 promotes WIP1-mediated medulloblastoma growth. 2237 89


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