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)

The Sonic Hedgehog (SHH) signaling pathway is indispensable for development, and functions to activate a transcriptional program modulated by the GLI transcription factors. Here, we report that loss of a regulator of the SHH pathway, Suppressor of Fused (Sufu), resulted in early embryonic lethality in the mouse similar to inactivation of another SHH regulator, Patched1 (Ptch1). In contrast to Ptch1+/- mice, Sufu+/- mice were not tumor prone. However, in conjunction with p53 loss, Sufu+/- animals developed tumors including medulloblastoma and rhabdomyosarcoma. Tumors present in Sufu+/-p53-/- animals resulted from Sufu loss of heterozygosity. Sufu+/-p53-/- medulloblastomas also expressed a signature gene expression profile typical of aberrant SHH signaling, including upregulation of N-myc, Sfrp1, Ptch2 and cyclin D1. Finally, the Smoothened inhibitor, hedgehog antagonist, did not block growth of tumors arising from Sufu inactivation. These data demonstrate that Sufu is essential for development and functions as a tumor suppressor.
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PMID:Loss of suppressor-of-fused function promotes tumorigenesis. 1745 75

Defective DNA damage responses in the nervous system can result in neurodegeneration or tumorigenesis. Despite the importance of DNA damage signalling, the neural function of many critical DNA repair factors is unclear. BRCA2 is necessary for homologous recombination repair of DNA and the prevention of diseases including Fanconi Anemia and cancer. We determined the role of BRCA2 during brain development by inactivating murine Brca2 throughout neural tissues. In striking contrast to early embryonic lethality after germ-line inactivation, Brca2(LoxP/LoxP);Nestin-cre mice were viable. However, Brca2 loss profoundly affected neurogenesis, particularly during embryonic and postnatal neural development. These neurological defects arose from DNA damage as Brca2(LoxP/LoxP);Nestin-cre mice showed extensive gammaH2AX in neural tissue and p53 deficiency restored brain histology but lead to rapid formation of medulloblastoma brain tumors. In contrast, loss of the Atm kinase did not markedly attenuate apoptosis after Brca2 loss, but did partially restore cerebellar morphology, supporting a genomic surveillance function for ATM during neurogenesis. These data illustrate the importance of Brca2 during nervous system development and underscore the tissue-specific requirements for DNA repair factors.
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PMID:BRCA2 is required for neurogenesis and suppression of medulloblastoma. 1747 7

The aim of the present study is to investigate the effect of histone deacetylase inhibitor, trichostatin A (TSA) on the cell growth, apoptosis, genomic DNA damage and the expression of telomerase and associated factors in human normal and brain cancer cells. Here, human normal un-transformed fibroblasts (MRC-5), human normal hTERT-immortalised fibroblasts (hTERT-BJ1) and human brain cancer cell lines (glioblastoma cell line, A-172 and medulloblastoma cell line, ONS-76) were treated with 0.5-3.0microM TSA for 24h. Exposure to TSA resulted in apoptosis in a dose-dependent manner in the brain cancer cells. Glioblastoma cell line (A-172) displayed higher sensitivity to TSA-induced cell killing effect and apoptosis than the medulloblastoma cell line (ONS-76). The brain cancer cell lines and hTERT-BJ1 cell line displayed significant inhibition in telomerase activity and hTERT mRNA level after 2microM TSA treatment. Elevated expressions of p53 and p21 with a decrease in cyclin-D level supported the observation on cell cycle arrest following TSA treatment. Upregulation of Bax and cytochrome c correlated with the apoptotic events in TSA-treated cells. This study suggests that telomerase and hTERT might be the primary targets of TSA which may have the potential to be used as a telomerase inhibitor in cancer therapy.
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PMID:Inhibition of telomerase activity and human telomerase reverse transcriptase gene expression by histone deacetylase inhibitor in human brain cancer cells. 1766 39

Medulloblastoma is the most common malignant brain tumor of childhood. Despite numerous advances, clinical challenges range from recurrent and progressive disease to long-term toxicities in survivors. The lack of more effective, less toxic therapies results from our limited understanding of medulloblastoma growth. Although TP53 is the most commonly altered gene in cancers, it is rarely mutated in medulloblastoma. Accumulating evidence, however, indicates that TP53 pathways are disrupted in medulloblastoma. Wild-type p53-induced phosphatase 1 (WIP1 or PPM1D) encodes a negative regulator of p53. WIP1 amplification (17q22-q23) and its overexpression have been reported in diverse cancer types. We examined primary medulloblastoma specimens and cell lines, and detected WIP1 copy gain and amplification prevalent among but not exclusively in the tumors with 17q gain and isochromosome 17q (i17q), which are among the most common cytogenetic lesions in medulloblastoma. WIP1 RNA levels were significantly higher in the tumors with 17q gain or i17q. Immunoblots confirmed significant WIP1 protein in primary tumors, generally higher in those with 17q gain or i17q. Under basal growth conditions and in response to the chemotherapeutic agent, etoposide, WIP1 antagonized p53-mediated apoptosis in medulloblastoma cell lines. These results indicate that medulloblastoma express significant levels of WIP1 that modulate genotoxic responsiveness by negatively regulating p53.
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PMID:Medulloblastomas overexpress the p53-inactivating oncogene WIP1/PPM1D. 1793 21

Medulloblastomas arise in the cerebellum and are the most common pediatric primary malignant brain tumors. Currently, medulloblastoma patients are best treated with surgical removal of the tumor, adjuvant radiation therapy and chemotherapy. The chemotherapeutic agents that showed efficiency against medulloblastomas include lomustine and vincristine. However, the effects of these drugs on medulloblastomas as well as on other cell types is still not well defined. In the present report we present evidence that the cytotoxic effect of these drugs is not specific for medulloblastoma cells but includes also normal fibroblast and epithelial cells. We have also shown that vincristine and lomustine trigger apoptosis in all these cells through the mitochondrial pathway via decrease in the level of the anti-apoptosis proteins Bcl-2 and Bcl-xl, respectively. Intriguingly, the proportion of apoptotic cells induced in medulloblastoma and normal epithelial and fibroblastic cells was similar. In addition, vincristine induced low proportion of necrosis in medulloblastoma and normal fibroblast cells. Interestingly, while vincristine induced cell cycle delay in G2/M phase in normal as well as medulloblastoma cells, lomustine effect on the cell cycle was specific for medulloblastoma cells. Furthermore, we have shown that vincristine and lomustine up-regulated p21 protein level in a p53-independent manner. These results shed more light on the biological effects of vincristine and lomustine and show that lomustine is a more specific and potent anti-medulloblastoma agent.
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PMID:Vincristine and lomustine induce apoptosis and p21(WAF1) up-regulation in medulloblastoma and normal human epithelial and fibroblast cells. 1805 69

Medulloblastomas are brain tumors that arise in the cerebellum of children and contain stem cells in a perivascular niche thought to give rise to recurrence following radiation. We used several mouse models of medulloblastomas in parallel to better understand how the critical cell types in these tumors respond to therapy. In our models, the proliferating cells in the tumor bulk undergo radiation-induced, p53-dependent apoptotic cell death. Activation of Akt signaling via PTEN loss transforms these cells to a nonproliferating extensive nodularity morphology. By contrast, the nestin-expressing perivascular stem cells survive radiation, activate PI3K/Akt pathway, undergo p53-dependent cell cycle arrest, and re-enter the cell cycle at 72 h. Furthermore, the ability of these cells to induce p53 is dependent on the presence of PTEN. These cellular characteristics are similar to human medulloblastomas. Finally, inhibition of Akt signaling sensitizes cells in the perivascular region to radiation-induced apoptosis.
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PMID:PI3K pathway regulates survival of cancer stem cells residing in the perivascular niche following radiation in medulloblastoma in vivo. 1828 60

Hedgehog-mediated signaling has been shown to promote growth and dissemination of solid cancers, most prominently basal cell carcinomas and medulloblastoma. Recent findings indicate that hedgehog signals are also important for tumor growth in hematologic malignancies. Hedgehog ligands secreted by stromal cells could elicit Patched/Smoothened-mediated antiapoptotic signaling in mouse B-cell lymphomas. Inhibition of hedgehog signaling induced apoptosis in lymphoma cells and prolonged survival of lymphoma-bearing mice. Depletion of tumor cells proceeded in the absence of p53 via the mitochondrial apoptotic pathway. These and other recently published data on hedgehog inhibition in cancer cells and their implications will be discussed.
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PMID:Stroma-initiated hedgehog signaling takes center stage in B-cell lymphoma. 1828 68

We report a case of glioblastoma (GBM) occurring 8 years after radiation therapy for a medulloblastoma. A 15-year-old boy underwent surgery and radiotherapy for a medulloblastoma and 8 years later he developed a second tumor at the same site. The second lesion showed different histological and molecular features, was diagnosed as a glioblastoma and fulfilled the criteria of radiation-induced neoplasm. Mutational analysis of the p53 gene showed a C to G transition at codon 176 in tumor DNA. LOH was detected at 17p and 19q. The tumor also showed O6-methylguanine-DNA methyl-transferase (MGMT) promoter methylation and no amplification of EGF receptor. In conclusion, the radiation-induced MGMT hyper-methylation and p53 mutations may have a role in the development of a subgroup of radio-induced glioma (RIG), suggesting that these molecular alterations directly cooperate in the genesis of the post-irradiation GBM. Moreover RIGs seem to be a heterogeneous group of tumors that may resemble either primary or secondary GBM.
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PMID:Radiation-induced glioblastoma in a medulloblastoma patient: a case report with molecular features. 1838 14

Gliomas and medulloblastomas are the most frequent malignant brain tumors in adult and children respectively. Although both tumors arise in the CNS, there is a significant difference in their therapeutic response. Medulloblastomas are relatively curable, while glioblastomas are basically incurable. During the last decade several reports have demonstrated the existence of cancer stem cells in brain tumors, their location and their response to treatment. We have recently described the therapeutic response of medulloblastomas to radiation in their native microenvironment, illustrating how p53 and Pi3K signaling pathways lead to the evasion of cell death by the nestin-expressing cells in the perivascular stem cell niche, even while the bulk of tumor succumbs to apoptosis.(1) It remains to be determined whether this mechanism of tumor resistance applies to the more complex stem-cell niche and tumor bulk of gliomas.
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PMID:Cancer stem cells and survival pathways. 1842 Dec 51

Medulloblastoma (MB) is the most common malignant brain tumor in childhood. The alterations found include: presence of oncoproteins p53 and HER2, elevated mitotic index, and presence of neuronal differentiation. The aim of this study was to determine the immunohistochemical expression of markers Ki-67, NeuN, synaptophysin, HER2 and p53 in 40 MB samples and their correlation with clinicopathologic parameters and survival. In 29 patients (72.5%), >20% of cells were positive for Ki-67. Males showed greater ki-67 expression (p=0.02) and smaller survival rates (p=0.002). NeuN and synaptophysin were negative in 16 (40%) and 8 (20%) cases, respectively. P53 was positive in 18 (45%) cases, with 11 (61%) weakly positive and 7 (39%) strongly positive. HER2 was positive in 23 (57.5%) of the samples and did not show statistical association with survival (p=0.07).
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PMID:Immunohistochemical expression of markers Ki-67, neun, synaptophysin, p53 and HER2 in medulloblastoma and its correlation with clinicopathological parameters. 1864 77


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