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)

Malignant triton tumors (MTT) are rare soft-tissue tumors characterized by a mixture of cells with nerve sheath and skeletal muscle differentiation. MTT is a histological variant of malignant peripheral nerve sheath tumors (MPNST). No characteristic cytogenetic anomaly has been detected in MPNST or MTT. In this paper, we report on the cytogenetic findings of an MTT from a 20-year old male with neurofibromatosis (NF1). The tumoral karyotype showed the modal number to be near-diploid and an abnormal karyotype with a Robertsonian translocation and 4 markers: 49,XY,der(14;15)(q10;q10),+4mar. Spectral karyotyping revealed the karyotype: 49,XY, der(14;15)(q10;q10),+i(8)(q10)x4. Fluorescence in situ hybridization analysis of the tissue confirmed the presence of the additional i(8)(q10) in all tumoral cells. The sequence analysis of p53 revealed a polymorphism in exon 9, codon 329. The two alleles, TTC and TCC, codify for phenylalanine and serine, respectively. Our results indicate that all neoplastic cells have the same cytogenetic pattern, suggesting that both cell lines, which show nerve sheath and skeletal muscle differentiation, are derived from a unique stem cell. The acquired Robertsonian chromosomal recombinants might represent an event in the tumorigenesis of MTT, and the present data suggest that genes located on 8q can be involved in the development of MTT.
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PMID:Acquisition of i(8q) as an early event in malignant triton tumors. 1547 51

Between 1991 and 2002, 456 patients with an intracranial meningioma were treated. Thirty-nine of these had more than one meningioma (8.6%). The mean age was 58 years (27-85 years). Sex distribution was 8.8:1 (35 female, four male). There was no associated spinal meningioma. No patient had neurofibromatosis. In 19 patients all meningiomas were removed. Twelve showed the same histology, seven had different histological features. In the remaining 20 patients only the symptomatic meningioma was removed. Recurrences occurred in 11 patients (28.2%). Six patients died during follow-up. Multiple meningiomas have their own clinical features. Besides a high female preponderance, PR expression was stronger in multiple meningiomas than in solitary meningiomas while p53 status and MIB-1 LI were similar between the two groups. Progesterone receptor, p53 status and MIB-1 LI were valuable markers for predicting a patient's outcome in multiple meningiomas. The number of meningiomas is growing in patients with recurrent meningiomas.
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PMID:Clinical and histological features of multiple meningiomas compared with solitary meningiomas. 1584 17

Type 1 neurofibromatosis (NF1) is a common autosomal dominant disorder that results in neuroectodermal tumors. The NF1 tumor-suppressor gene encodes neurofibromin, which includes a GTPase-activating domain for Ras inactivation. Affinity purification showed N-Ras to be the predominant activated isoform of Ras in two independent neurofibrosarcoma cell lines from NF1 patients (lines ST88-14 and NF90-8). These NF1 cells also demonstrated increased constitutive activity of the extracellular signal-regulated kinases 1 and 2 (ERK1,2) mitogen-activated protein (MAP) kinases compared with a sporadic malignant schwannoma cell line that maintains neurofibromin expression (STS-26T). Thus, MAP kinase kinase (MEK) inhibitors may be a rational approach to NF1 therapy. The MEK inhibitors PD98059 [2'-amino-3'-methoxyflavone], PD184352 (also called CI-1040) [2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-benzamide], and U0126 [1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene] all produced concentration-dependent suppression of the proliferation of the three cell lines. Individual MEK inhibitors had similar effects in all three cell lines. However, only the antiproliferative effects of PD184352 correlated closely with the elimination of ERK1,2 MAP kinase activities. PD98059 was primarily cytostatic, whereas U0126 and PD184352 were cytotoxic. Only PD184352 induced apoptosis in all three lines, as indicated by morphology, activation of DEVDase, procaspase-3 cleavage, and the appearance of populations having sub-G(0)/G(1) DNA contents. The differential effects of the MEK inhibitors on cell survival were not dependent on p53 status or effects on the ERK5 pathway. PD184352 was also proapoptotic to primary rat Schwann cells. Hence, although PD184352 effectively killed neurofibrosarcoma cells, its effects on normal Schwann cells may limit its usefulness in the clinic.
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PMID:The mitogen-activated protein kinase/extracellular signal-regulated kinase kinase inhibitor PD184352 (CI-1040) selectively induces apoptosis in malignant schwannoma cell lines. 1623 99

The majority of cancers are caused by mutations of a few signal transducers such as the GTPase RAS, the kinase Src and the tumor suppressor p53. Thus, a group of specific chemical compounds called 'signal therapeutics', that block or reverse selectively these abnormally activated signaling pathways would be very useful for the treatment of these signally disordered cancers. More than 90% of human pancreatic cancers are associated with oncogenic mutations of RAS, in particular K-RAS at codon 12. We have previously shown that, PAK1, the Rac/CDC42-dependent Ser/Thr kinase, is essential for RAS/estrogen-induced transformation and neurofibromatosis (NF). Furthermore, we and others have demonstrated that the growth of mouse RAS-induced sarcomas allografts in mice is almost completely suppressed by either FK228 or a combination of two complimentary Tyr-kinase inhibitors, PP1 and AG 879, all of which block the RAS-induced activation of PAK1. Since, so far no effective therapeutic is available for the treatment of pancreatic cancer patients, we have examined the therapeutic potential of either FK228, the combination of these two Tyr-kinase inhibitors or GL-2003, a water-soluble derivative of AG 879, on human pancreatic cancer (Capan-1) xenograft in mice. Among these PAK1-blocking approaches, the PP1/GL-2003 combination is the most effective in the therapy of this cancer xenograft model. Its therapeutic potential is equivalent to those of gemcitabine and kigamicin D which suppress by 70-80% the growth of a similar human pancreatic cancer xenograft model. Also, this PP1/GL-2003 combination therapy has been proven to be very effective to suppress the estrogen-independent growth of an NF1-deficient multidrug/FK228-resistant human breast cancer (MDA-MB-231) xenograft in mice.
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PMID:Signal therapy of human pancreatic cancer and NF1-deficient breast cancer xenograft in mice by a combination of PP1 and GL-2003, anti-PAK1 drugs (Tyr-kinase inhibitors). 1654 Feb 33

Tumors of the nervous system most often occur in both children and adults as sporadic events with no family history of the disease, but they are also among the clinical manifestations of a significant number of familial cancer syndromes, including familial retinoblastoma, neurofibromatosis 1 and 2, tuberous sclerosis, and Cowden, Turcot, Li-Fraumeni and nevoid basal cell carcinoma (Gorlin) syndromes. All of these syndromes involve transmissible genetic risk resulting from loss of a functional allele, or inheritance of a structurally defective allele, of a specific gene. These genes include RB1, NF1, NF2, TSC1, TSC2, TP53, PTEN, APC, hMLH1, hPSM2, and PTCH, most of which function as tumor suppressor genes. The same genes are also observed in mutated and inactive forms, or are deleted, in tumor cells in sporadic cases of the same tumors. The nature of the mutational events that give rise to these inactivated alleles suggests a possible role of environmental mutagens in their causation. However, only external ionizing radiation at high doses is clearly established as an environmental cause of brain, nerve and meningeal tumors in humans. Transplacental carcinogenesis studies in rodents and other species emphasize the extraordinary susceptibility of the developing mammalian nervous system to carcinogenesis, but the inverse relationship of latency to dose suggests that low transplacental exposures to genotoxicants are more likely to result in brain tumors late in life, rather than in childhood. While not all neurogenic tumor-related genes in humans have similar effects in experimental rodents, genetically engineered mice (GEM) increasingly provide useful insights into the combined effects of multiple tumor suppressor genes and of gene-environment interactions in the genesis of brain tumors, especially pediatric brain tumors such as medulloblastoma.
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PMID:Inducible and transmissible genetic events and pediatric tumors of the nervous system. 1701 46

A case of two sporadic cellular neurofibromas with atypia and one widespread hyalinization neurofibroma of the lumbar spine in a 51-year-old man without evidence of neurofibromatosis-1 is reported. Cellular neurofibroma with atypia is an unusual variant. The definite criteria for low-grade and high-grade malignant peripheral nerve sheath tumors as well as cellular neurofibroma are not well defined in the literature. The clinical significance of atypical cellular neurofibroma has rarely been systematically studied. To our knowledge, the concomitance of cellular architecture and cytologic atypia is rarely documented, and this is a rare report of atypical cellular neurofibroma. The recognition of this entity is of great importance to both pathologists and clinicians because atypical cellular neurofibroma is clever at masquerading both histologically and cytologically as a sarcoma; therefore, a precise diagnosis of this variant is essential because of the differences in treatment and clinical behavior between benignancy and malignancy. We also examined the immunohistochemical characteristics of CD34 positive cells and focal high expression of p53 up to 73% encountered in our case. To our knowledge, seldom have series or case reports elucidated this phenomenon.
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PMID:Cellular neurofibroma with atypia mimics sarcoma: report of a case with immunohistochemical staining pattern analysis and literature review. 1709 83

Carcinoid and islet-cell carcinoma are often also known as low-grade neuroendocrine carcinomas. They are often slow-growing but can be resistant to standard therapy. While somatostatin analogues are often used to control hormonal syndromes, there is currently no therapy approved in the US for control of carcinoid tumor growth. For islet-cell carcinoma, streptozocin-based chemotherapy may induce tumor shrinkage, but second-line option are limited. This chapter reviews the molecular biology of neuroendocrine tumors, including the roles of MENIN, TSC2, NF-1, vHL, p53, bcl-2, bax, VEGF, IGF, PDGF, EGFR, and mTOR. Recently, there has been interest in developing molecularly targeted therapy for this group of diseases. Phase-II studies with imatinib, bevacizumab, sunitinib, gefitnib, temsirolimus, and everolimus (RAD001) have completed accrual. Encouraging results have been observed in studies with VEGF and mTOR inhibitors. Phase-III study of bevacizumab is planned in the US. Large-scale multinational phase-II and -III studies of everolimus are under way.
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PMID:Neuroendocrine tumors. Molecular targeted therapy for carcinoid and islet-cell carcinoma. 1738 71

Gene expression profiling of metastatic brain tumors from primary lung adenocarcinoma, using a 17k-expression array, revealed that 1561 genes were consistently altered. Further functional classification placed the genes into seven categories: cell cycle and DNA damage repair, apoptosis, signal transduction molecules, transcription factors, invasion and metastasis, adhesion, and angiogenesis. Genes involved in apoptosis, such as caspase 2 (CASP2), transforming growth factor-beta inducible early gene (TIEG), and neuroprotective heat shock protein 70 (Hsp70) were underexpressed in metastatic brain tumors. Alterations in Rho GTPases (ARHGAP26, ARHGAP1), as well as down-regulation of the metastasis suppressor gene KiSS-1 were noted, which may contribute to tumor aggression. Overexpression of the invasion-related gene neurofibromatosis 1 (NF1), and angiogenesis-related genes vascular endothelial growth factor-B (VEGF-B) and placental growth factor (PGF) was also evidenced. Brain-specific angiogenesis inhibitors 1 and 3 (BAI1 and BAI3) were underexpressed as well. Examination of cell-adhesion and migration-related genes revealed an increased expression of integrins and extracellular matrices collagen and laminin. The study also showed alterations in p53 protein-associated genes, among these increased gene expression of p53, up-regulation of Reprimo or candidate mediator of the p53-dependent G2-arrest, down-regulation of p53-regulated apoptosis-inducing protein 1 (p53AIP1), decreased expression of tumor protein inducible nuclear protein 1 (p53DINP1), and down-regulation of Mdm4 (MDMX). The results demonstrated that genes involved in adhesion, motility, and angiogenesis were consistently up-regulated in metastatic brain tumors, while genes involved in apoptosis, neuroprotection, and suppression of angiogenesis were markedly down-regulated, collectively making these cancer cells prone to metastasis.
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PMID:Gene expression profiling of metastatic brain cancer. 1761 51

Meningiomas account for approximately 30% of all primary central nervous system tumors and are found in half of neurofibromatosis type 2 patients often causing significant morbidity. Although most meningiomas are benign, 10% are classified as atypical or anaplastic, displaying aggressive clinical behavior. Biallelic inactivation of the neurofibromatosis 2 (NF2) tumor suppressor is associated with meningioma formation in all NF2 patients and 60% of sporadic meningiomas. Deletion of the p16(INK4a)/p14(ARF) locus is found in both benign and malignant meningiomas, while mutation of the p53 tumor suppressor gene is uncommon. Previously, we inactivated Nf2 in homozygous conditional knockout mice by adenoviral Cre delivery and showed that Nf2 loss in arachnoid cells is rate-limiting for meningioma formation. Here, we report that additional nullizygosity for p16(Ink4a) increases the frequency of meningioma and meningothelial proliferation in these mice without modifying the tumor grade. In addition, by using magnetic resonance imaging (MRI) to screen a large cohort of mutant mice, we were able to detect meningothelial proliferation and meningioma development opening the way to future studies in which therapeutic interventions can be tested as preclinical assessment of their potential clinical application.
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PMID:Natural history of meningioma development in mice reveals: a synergy of Nf2 and p16(Ink4a) mutations. 1792 78

A rhabdomyoblastic differentiation in a malignant peripheral nerve sheath tumor is unusual and is termed as a malignant triton tumor. A series of 10 such cases with their clinicomorphological features, diagnosed over a 10-year period, is presented. The average age of occurrence was 30 years, with the maximum number of cases in the second decade and with male outnumbering female patients. More cases were seen in the setting of neurofibromatosis. On histology, 80% of the cases were of high grade. Distinct rhabdomyoblastic cells were identified in the areas of malignant peripheral nerve sheath tumor. Immunohistochemistry confirmed the neurogenic differentiation with varying S-100 expression and the rhabdomyoblastic differentiation with desmin and myoglobin positivity in all cases. Surgery with adequate margins constituted the treatment mainstay with adjuvant chemotherapy and/or radiotherapy in individual cases. On follow-up with 7 cases, 3 showed local recurrences, including one that, in addition to another 2 cases, showed lung metastasis. One patient died of the disease. This case along with another high-grade case displayed a diffuse Ki-67 and p53 positivity. Malignant triton tumor is an uncommon tumor associated with an aggressive behavior. Surgery with clear margins is the treatment mainstay. Adjuvant radiotherapy is effective.
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PMID:Clinicomorphologic features of a series of 10 cases of malignant triton tumors diagnosed over 10 years at a tertiary cancer hospital in Mumbai, India. 1832 68


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