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)

Although deregulation of Hedgehog signalling is considered to play a crucial oncogenic role and commonly occurrs in medulloblastoma, genetic lesions in components of this pathway are observed in a minority of cases. The recent identification of a novel putative tumor suppressor (REN(KCTD11)) on chromosome 17p13.2, a region most frequently lost in human medulloblastoma, highlights the role of allelic deletion of the gene in this brain malignancy, leading to the loss of growth inhibitory activity via suppression of Gli-dependent activation of Hedgehog target genes. The presence on 17p13 of another tumor suppressor gene (p53) whose inactivation cooperates with Hedgehog pathway for medulloblastoma formation, suggests that 17p deletion unveils haploinsufficiency conditions leading to abrogation of either direct and indirect checkpoints of Hedgehog signalling in cancer.
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PMID:Chromosome 17p deletion in human medulloblastoma: a missing checkpoint in the Hedgehog pathway. 1546 54

Methionine deprivation imposes a metabolic stress, termed methionine stress, that inhibits mitosis and induces cell cycle arrest and apoptosis. The methionine-dependent central nervous system tumor cell lines DAOY (medulloblastoma), SWB61 (anaplastic oligodendroglioma), SWB40 (anaplastic astrocytoma), and SWB39 (glioblastoma multiforme) were compared with methionine-stress resistant SWB77 (glioblastoma multiforme). The cDNA-oligoarray analysis and reverse transcription-PCR verification indicated common changes in gene expression in methionine-dependent cell lines to include up-regulation/induction of cyclin D1, mitotic arrest deficient (MAD)1, p21, growth arrest and DNA-damage-inducible (GADD)45 alpha, GADD45 gamma, GADD34, breast cancer (BRCA)1, 14-3-3sigma, B-cell CLL/lymphoma (BCL)1, transforming growth factor (TGF)-beta, TGF-beta-induced early response (TIEG), SMAD5, SMAD7, SMAD2, insulin-like growth factor binding protein (IGFBP7), IGF-R2, vascular endothelial growth factor (VEGF), TNF-related apoptosis-inducing ligand (TRAIL), TNF-alpha converting enzyme (TACE), TRAIL receptor (TRAIL-R)2, TNFR-related death receptor (DR)6, TRAF interacting protein (I-TRAF), IL-6, MDA7, IL-1B convertase (ICE)-gamma, delta and epsilon, IRF1, IRF5, IRF7, interferon (IFN)-gamma and receptor components, ISG15, p65-NF-kappaB, JUN-B, positive cofactor (PC)4, C/ERB-beta, inositol triphosphate receptor I, and methionine adenosyltransferase II. On the other hand, cyclins A1, A2, B1 and B2, cell division cycle (CDC)2 and its kinase, CDC25 A and B, budding uninhibited by benzimidazoles (BUB)1 and 3, MAD2, CDC28 protein kinase (CKS)1 and 2, neuroepithelial cell transforming gene (NET)1, activator of S-phase kinase (ASK), CDC14B phosphatase, BCL2, TGF-beta activated kinase (TAK)1, TAB1, c-FOS, DNA topoisomerase II, DNA polymerase alpha, dihydrofolate reductase, thymidine kinase, stathmin, and MAP4 were down-regulated. In the methionine stress-resistant SWB77, only 20% of the above genes were affected, and then only to a lesser extent. In addition, some of the changes observed in SWB77 were opposite to those seen in methionine-dependent tumors, including expression of p21, TRAIL-R2, and TIEG. Despite similarities, differences between methionine-dependent tumors were substantial, especially in regard to regulation of cytokine expression. Western blot analysis confirmed that methionine stress caused the following: (a) a marked increase of GADD45alpha and gamma in the wt-p53 cell lines SWB61 and 40; (b) an increase in GADD34 and p21 protein in all of the methionine-dependent lines; and (c) the induction of MDA7 and phospho-p38 in DAOY and SWB39, consistent with marked transcriptional activation of the former under methionine stress. It was additionally shown that methionine stress down-regulated the highly active phosphatidylinositol 3'-kinase pathway by reducing AKT phosphorylation, especially in DAOY and SWB77, and also reduced the levels of retinoblastoma (Rb) and pRb (P-ser780, P-ser795, and P-ser807/811), resulting in a shift in favor of unphosphorylated species in all of the methionine-dependent lines. Immunohistochemical analysis showed marked inhibition of nuclear translocation of nuclear factor kappaB under methionine stress in methionine-dependent lines. In this study we show for the first time that methionine stress mobilizes several defined cell cycle checkpoints and proapoptotic pathways while coordinately inhibiting prosurvival mechanisms in central nervous system tumors. It is clear that methionine stress-induced cytotoxicity is not restricted by the p53 mutational status.
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PMID:Modulation of gene expression in human central nervous system tumors under methionine deprivation-induced stress. 1549 78

Embryonal tumors, the most common group of malignant brain tumors in childhood, are heterogeneous and have been associated with a large number of genetic abnormalities. The aim of this study was to comprehensively analyze loss of heterozygosity (LOH) on regions harboring suppressor genes (PTCH2, PTCH1, APC, PTEN, DMBT1, SUFU, AXIN1, hSNF5/INI1) and to study chromosomal regions in which deletions have been described most frequently (1p, 1q, 11p, 16p, 17p). Twenty-nine children (17 male and 12 female), aged from 1 year 13 years were included in this study. There were 24 medulloblastomas (MB) and 5 supratentorial primitive neuroectodermal tumors (sPNET). Tissue samples from 29 primary and 11 recurrent tumors were analyzed according to the LOH standard procedures, which were extended to include fluorescence in situ hybridization for detection of isochromosome 17q (i(17q)) and direct sequencing ofTP53 exon 4. LOH on 17p was found in 15 out of 29 tumors. FISH analysis identified the presence of i(17q) in 16 tumors. Comparison of LOH analysis and the FISH data indicated that alterations of 17p were related to be the introduction of an i(17q) formation. LOH on 10q and 9q was observed in 4 and 2 cases, respectively, and was associated with alterations of chromosome 17. These results indicated a connection between alterations of PTCH/SHH genes and abnormalities of chromosome 17. A deleted region on 22q, covering the hSNF5/INI1 locus, was observed in 3 tumors. Progression of the molecular changes occurred in 1 case of recurrent medulloblastoma. LOH on 10q and 17p was found in both primary and recurrent tumor, while losses on 11p, 16p, and 16q occurred only in the recurrent tumor. No evidence of alteration in TP53 exon 4 was identified.
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PMID:Molecular abnormalities in pediatric embryonal brain tumors--analysis of loss of heterozygosity on chromosomes 1, 5, 9, 10, 11, 16, 17 and 22. 1558 Oct 23

The full spectrum of developmental potential includes normal as well as abnormal and disease states. We therefore subscribe to the idea that tumors derive from the operation of paradevelopmental programs that yield consistent and recognizable morphologies. Work in frogs and mice shows that Hedgehog (Hh)-Gli signaling controls stem cell lineages and that its deregulation leads to tumor formation. Moreover, human tumor cells require sustained Hh-Gli signaling for proliferation as cyclopamine, an alkaloid of the lily Veratrum californicum that blocks the Hh pathway, inhibits the growth of different tumor cells in vitro as well as in subcutaneous xenografts. However, the evidence that systemic treatment is an effective anti-cancer therapy is missing. Here we have used Ptc1(+/-); p53(-/-) mice which develop medulloblastoma to test the ability of cyclopamine to inhibit endogenous tumor growth in vivo after tumor initiation through intraperitoneal delivery, which avoids the brain damage associated with direct injection. We find that systemic cyclopamine administration improves the health of Ptc1(+/-);p53(-/-) animals. Analyses of the cerebella of cyclopamine-treated animals show a severe reduction in tumor size and a large decrease in the number of Ptc1-expressing cells, as a readout of cells with an active Hu-Gli pathway, as well as an impairment of their proliferative capacity, always in comparison with vehicle treated mice. Our data demonstrate that systemic treatment with cyclopamine inhibits tumor growth in the brain supporting its therapeutical value for human HH-dependent tumors. They also demonstrate that even the complete loss of the well-known tumor suppressor p53 does not render the tumor independent of Hh pathway function.
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PMID:In vivo inhibition of endogenous brain tumors through systemic interference of Hedgehog signaling in mice. 1565 9

The MYCN oncogene plays an important role in the pathogenesis of neuroblastoma. It is amplified in more than 30% of high-risk cases and over expression induces neuroblastoma in transgenic mice. MYCN amplification/overexpression is found in many types of cancers including neuroblastoma, medulloblastoma and other aggressive tumors of neuroectodermal origin as well as in rhadomyosarcoma and small cell lung cancers. MYCN exerts its oncogenic effects through transcriptional regulation of numerous target genes. We have recently characterized the p53 inhibitor MDM2 (HDM2) as one such target in MYCN amplified neuroblastoma cell lines. Conditional expression of MYCN yields elevated MDM2 mRNA and protein. MYCN inhibition leads to diminished MDM2, stabilized p53 and apoptosis. As the primary negative regulator of p53, MDM2 is critically regulated in normal cells to ensure adequate p53 activity in response to damage or stress. Additionally, MDM2 regulates many p53 independent processes pertinent to oncogenesis. We propose that increased MDM2 levels downstream of MYCN are tumorigenic secondary to disruption of multiple p53 dependent and independent mechanisms controlling genomic stability, apoptopsis and cell cycle progression. Further research into the MYCN/MDM2 regulated pathways will provide insight into the pathogenesis of MYCN-driven tumors and provide targets for novel therapeutic interventions.
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PMID:MDM2 as a critical effector of the MYCN oncogene in tumorigenesis. 1591 61

Radiation-induced glioblastoma multiforme (GBM) is a rare complication of radiotherapy. The authors report such a case occurring 10 years after treatment of cerebellar medulloblastoma. The patient was a 15-year-old boy who had undergone a gross-total removal of a medulloblastoma and received radiation therapy at the age of 5 years. He had experienced no tumor recurrences for 10 years until a new enhancing mass was found at the original site of the medulloblastoma. Following its resection the new lesion was found to be a GBM and there was no evidence of a medulloblastoma. The second tumor developed at the same site as the previous one after a sufficient latent period and fulfilled the criteria for a radiation-induced neoplasm. The original tumor cells expressed synaptophysin without p53 overexpression, a characteristic feature of medulloblastomas. In contrast, cells from the later tumor expressed glial fibrillary acidic protein and p53 but not synaptophysin. A sequence analysis of the p53 gene showed deletion at codon 233 and a C to G transition at codon 278 in the GBM but no mutation in the medulloblastoma. A GBM specimen revealed no amplification of the epidermal growth factor receptor compared with a normal control specimen. In conclusion, the clinical features of a radiation-induced GBM are similar to that of the primary GBM, whereas its genetic alterations render it a secondary GBM. These findings indicate that radiation-induced GBM should be considered a distinct clinical entity.
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PMID:Radiation-induced cerebellar glioblastoma at the site of a treated medulloblastoma: case report. 1592 95

Recurrent genetic alterations in human medulloblastoma (MB) include mutations in the sonic hedgehog (SHH) signaling pathway and TP53 inactivation (approximately 25% and 10% of cases, respectively). However, mouse models of MB, regardless of their initiating lesions, generally depend upon p53 inactivation for rapid onset and high penetrance. The gene encoding the cyclin-dependent kinase inhibitor p18(Ink4c) is transiently expressed in mouse cerebellar granule neuronal precursor cells (GNPs) as they exit the cell division cycle and differentiate. Coinactivation of Ink4c and p53 provided cultured GNPs with an additive proliferative advantage, either in the presence or absence of Shh, and induced MB with low penetrance but with greatly increased incidence following postnatal irradiation. In contrast, mice lacking one or two functional Ink4c alleles and one copy of Patched (Ptc1) encoding the Shh receptor rapidly developed MBs that retained wild-type p53. In tumor cells purified from double heterozygotes, the wild-type Ptc1 allele, but not Ink4c, was inactivated. Therefore, when combined with Ptc1 mutation, Ink4c is haploinsufficient for tumor suppression. Methylation of INK4C (CDKN2C) was observed in four of 23 human MBs, and p18(INK4C) protein expression was extinguished in 14 of 73 cases. Hence, p18(INK4C) loss may contribute to MB formation in children.
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PMID:The tumor suppressors Ink4c and p53 collaborate independently with Patched to suppress medulloblastoma formation. 1626 Apr 94

Valproic acid is a well-tolerated anticonvulsant that has been identified recently as a histone deacetylase inhibitor. To evaluate the antitumor efficacy and mechanisms of action of valproic acid in medulloblastoma and supratentorial primitive neuroectodermal tumor (sPNET), which are among the most common malignant brain tumors in children with poor prognosis, two medulloblastoma (DAOY and D283-MED) and one sPNET (PFSK) cell lines were treated with valproic acid and evaluated with a panel of in vitro and in vivo assays. Our results showed that valproic acid, at clinically safe concentrations (0.6 and 1 mmol/L), induced potent growth inhibition, cell cycle arrest, apoptosis, senescence, and differentiation and suppressed colony-forming efficiency and tumorigenicity in a time- and dose-dependent manner. The medulloblastoma cell lines were more responsive than the sPNET cell line and can be induced to irreversible suppression of proliferation and significantly reduced tumorigenicity by 0.6 and 1 mmol/L valproic acid. Daily i.p. injection of valproic acid (400 mg/kg) for 28 days significantly inhibited the in vivo growth of DAOY and D283-MED s.c. xenografts in severe combined immunodeficient mice. With Western hybridization and real-time reverse transcription-PCR, we further showed that the antitumor activities of valproic acid correlated with induction of histone (H3 and H4) hyperacetylation, activation of p21, and suppression of TP53, CDK4, and CMYC expression. In conclusion, valproic acid possesses potent in vitro and in vivo antimedulloblastoma activities that correlated with induction of histone hyperacetylation and regulation of pathways critical for maintaining growth inhibition and cell cycle arrest. Therefore, valproic acid may represent a novel therapeutic option in medulloblastoma treatment.
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PMID:Valproic acid induces growth arrest, apoptosis, and senescence in medulloblastomas by increasing histone hyperacetylation and regulating expression of p21Cip1, CDK4, and CMYC. 1637 6

Medulloblastoma is a malignant tumor that arises in the cerebellum in children, presumably by transformation of granule neuron precursor cells. In vivo models of medulloblastoma in genetically engineered mice have shown that activation of signal transduction pathways that stimulate proliferation and inhibit differentiation of neural progenitor cells during cerebellar development initiate medulloblastoma formation. Activation of the Sonic hedgehog (Shh)/Patched signaling pathway in the postnatal cerebellum is sufficient to induce medulloblastoma in mice. Activation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway by insulin-like growth factor-II, inactivation of the p53 tumor suppressor protein, loss of DNA damage repair mechanisms, and ectopic expression of Myc oncoproteins cooperate with Shh/Patched signaling to enhance tumor formation in mice. Ectopic expression of alpha and beta interferons in the developing brain also induces Shh-mediated medulloblastoma formation, suggesting a possible role for antiviral response in the genesis of medulloblastoma. By revealing which cell signaling proteins can initiate medulloblastoma formation, mouse models have enabled investigators to identify molecular targets for designing new therapies. Small-molecule inhibitors of the Shh/Patched and PI3K pathways are potential chemotherapeutic agents for patients with medulloblastoma.
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PMID:Modeling medulloblastoma with genetically engineered mice. 1639 71

Hemizygous Ptc1 mice have many features of Gorlin syndrome, including predisposition to medulloblastoma development. Ionizing radiation synergize with Ptc1 mutation to induce medulloblastoma only in neonatally exposed mice. To explore the mechanisms underlying age-dependent susceptibility, we irradiated Ptc(neo67/+) mice at postnatal day 1 (P1) or 10 (P10). We observed a dramatic difference in medulloblastoma incidence, which ranged from 81% in the cerebellum irradiated at P1 to 3% in the cerebellum irradiated at P10. A striking difference was also detected in the frequency of cerebellar preneoplastic lesions (100 versus 14%). Our data also show significantly lower induction of apoptosis in the cerebellum of medulloblastoma-susceptible (P1) compared to -resistant (P10) mice, strongly suggesting that medulloblastoma formation in Ptc1 mutants may be associated with resistance to radiation-induced cell killing. Furthermore, in marked contrast with P10 mice, cerebellum at P1 displays substantially increased activation of the cell survival-promoting Akt/Pkb protein, and markedly decreased p53 levels in response to radiation-induced genotoxic stress. Overall, these results show that developing cerebellar granule neuron precursors' (CGNPs) radiosensitivity to radiation-induced cell death increases with progressing development and inversely correlates with their ability to neoplastically transform.
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PMID:Linking DNA damage to medulloblastoma tumorigenesis in patched heterozygous knockout mice. 1640 52


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