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)

Rare inherited syndromes that to some extent explain familial glioma include Turcot's syndrome, Li-Fraumeni syndrome and neurofibromatosis types I and II. The majority of families with glioma do not meet the clinical criteria for any of these syndromes. In order to study the genetic origin of familial glioma, tumour DNA (n = 35) or blood samples (n = 8) were collected from 25 families. The glioma tumours were tested for microsatellite instability (MSI) with two markers, BAT25 and BAT26, since glioma is associated with hereditary non-polyposis colon cancer (HNPCC) in Turcot's syndrome. Furthermore, p53 was screened from blood DNA (exons 2-11) with temporal temperature gradient electrophoresis (TTGE) since germline mutations in p53 are seen in Li-Fraumeni syndrome. In gliomas, there is a wide variety of somatic mutations, such as, for instance, in p53, the epidermal growth factor receptor (EGFR) and p16. The tumour suppressor gene PTEN is also often somatically mutated in glioma, therefore it is attractive as a candidate gene for germline mutations in familial glioma. Blood DNA was directly sequenced for mutations in PTEN exons 1-9. The analysis showed that no mutations were found in either of the studied tumour suppressor genes, and no MSI-positive tumours were found. A common polymorphism in p53 at codon 72 (arginine/proline) was found in 6/8 of the patients. Apparently, mutation in the tested tumour suppressor genes or DNA mismatch repair genes does not explain the familial glioma observed in these families.
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PMID:Microsatellite instability, PTEN and p53 germline mutations in glioma families. 1166 37

Inactivation of the neurofibromatosis-1 (NF1) gene de-regulates RAS and cooperates with mutation or loss of the p53 tumor suppressor to induce tumorigenesis. p19(ARF) acts upstream of p53 in an oncogene checkpoint to induce apoptosis in response to activated RAS and other factors that stimulate proliferation. Therefore, we bred p19(ARF-/-) to NF1(+/-) mice to determine if loss of these genes collaborates in tumorigenesis. As expected from the embryonic lethality of NF1 null mice, no mice lacking both p19(ARF) and NF1 were born. Unexpectedly, the loss of one allele of NF1 did not greatly shorten the time to tumor formation in a p19(ARF) null background. The tumor types observed were characteristic of p19(ARF) null animals, not those associated with neurofibromatosis or those observed with NF1(+/-)/p53(+/-) mice. However, seven out of 12 animals developed multiple tumors, some with metastases. This multiple tumor phenotype was not previously observed with p19(ARF)-null mice and suggests a distinct form of cooperation between the loss of these tumor suppressors.
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PMID:Loss of neurofibromatosis-1 and p19(ARF) cooperate to induce a multiple tumor phenotype. 1211 76

Preimplantation genetic diagnosis (PGD) has recently been offered for couples with an inherited predisposition for late onset disorders. This paper presents the results of PGD for a group of couples at risk for producing children with cancer predisposition. Using a standard IVF procedure, oocytes or embryos were tested for different mutations predisposing to cancer, preselecting and transferring only mutation-free embryos back to the patients. The procedure was performed for patients with predisposition to familial adenomatous polyposis coli (FAP), Von Hippel-Lindau syndrome (VHL), retinoblastoma, Li-Fraumeni syndrome, determined by p53 tumour suppressor gene mutations, neurofibromatosis types I and II and familial posterior fossa brain tumour (hSNF5). Overall, 20 PGD cycles were performed for 10 couples, resulting in preselection and transfer of 40 mutation-free embryos, which resulted in five unaffected clinical pregnancies and four healthy children born by the present time. Despite the controversy of PGD use for late onset disorders, the data demonstrate the usefulness of this approach as the only acceptable option for at-risk couples to avoid the birth of children with an inherited predisposition to cancer, and to have a healthy child.
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PMID:Preimplantation genetic diagnosis for cancer predisposition. 1241 39

Germ-line mutations (present in all cells) in genes that are crucial for the cell cycle cause cancer only in specific cell lines (e.g. mismatch repair genes in the colon; BRCA1-2 in breast and ovary; other cancers in Bloom syndrome, neurofibromatosis and xeroderma pigmentosum). The mutation rate of genes other than mismatch repair or p53 is the same in colon cancer and in normal cells, indicating that a 'mutator phenotype', increasing the rate of mutations in many genes, is not an essential feature of sporadic cancers; conversely, fusion genes, TEL-AML1/AML1-ETO, typical of leukemia, are 100 times more frequent at birth than in overt leukemia in children, indicating that further selective events are needed to cause malignancy. The devastating impairment of immunity, as in AIDS patients, does not cause cancer other than Kaposi's sarcoma and non-Hodgkin's lymphoma, although immunological control is considered to be an essential mechanism in preventing the spread of cancer cells. These observations suggest that cell-specific additional events are needed to explain carcinogenesis. Carcinogenesis has been traditionally interpreted as the sequence of initiation (mutation) and promotion (clone expansion), with an interesting similarity with the neo-Darwinian theory of evolution, based on a first stage of genetic change (including recombination) and a second stage of selection. I propose that carcinogenesis consists in two general phases (not necessarily stages), i.e. genetic change followed by clone expansion (selective advantage). As in neo-Darwinian theory selection is chiefly represented by the elimination of the less fit, the selection of mutated cells would mainly consist in resistance to apoptosis or other types of 'bottlenecks' that hamper a cell's survival; an example of such a bottleneck is the autoimmunity that induces paroxysmal nocturnal hemoglobinuria in individuals with PIG-A mutations. Cancer rates show great variation in different countries around the world, a variation only marginally explained by genetic differences. More interestingly, migrants change their risk of cancer by adapting to that of the population into which they move: as these changes are not likely to be entirely due to mutagens in the environment, we have to invoke selective pressure over mutated cells to explain them. My theory is that mutated cells adapt to environmental 'niches' better than normal cells, in a 'gene-environment interaction' that involves the history of the genetic changes the cell has undergone and the kind of environment in which it happens to live.
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PMID:Cancer as an evolutionary process at the cell level: an epidemiological perspective. 1253 42

Preimplantation genetic diagnosis (PGD) has recently been performed for inherited cancer predisposition determined by p53 tumour suppressor gene mutations, suggesting the usefulness of PGD for late onset disorders with genetic predisposition, including those caused by the germline mutations of other tumour suppressor genes. Here PGD was performed for two couples, one at risk for producing a child with maternally derived neurofibromatosis type I (NF1), and the other with paternally derived neurofibromatosis type II (NF2). The procedure involved a standard IVF protocol, combined with testing of oocytes or embryos prior to their transfer back to the patients. Maternal mutation Trp-->Ter (TGG-->TGA) in exon 29 of the NF1 gene was tested by sequential PCR analysis of the first and second polar bodies, and paternal L141P mutation in exon 4 of the NF2 gene by embryo biopsy at the cleavage stage. In both cases, multiplex nested PCR was applied, involving NF1 and NF2 mutation analysis simultaneously with the 3 and 2 linked markers, respectively. Of 57 oocytes tested in four PGD cycles for NF1 mutation, 26 mutation-free oocytes were detected, from which eight were preselected for transfer, two in each cycle. These produced two clinical pregnancies, one confirmed to be mutation free by chorionic villus sampling but ending in a stillbirth, and the other still ongoing. Of 18 embryos analysed in a cycle performed for NF2 mutation, eight mutation-free embryos were detected, three of which were transferred back to the patient, resulting in a singleton pregnancy and the birth of a mutation-free child. This suggests that PGD is a useful approach for avoiding the birth of children with inherited cancer predisposition, determined by NF1 and NF2 gene mutations.
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PMID:Preimplantation diagnosis for neurofibromatosis. 1270 70

The RB1 pathway and the p53 pathway represent important, interconnected biochemical units frequently perturbed in human cancer. Essential tumor protective mechanisms, such as cellular growth control and apoptosis, are regulated through these systems. Comprehensive studies of these pathways, including most known pathway components, have not been performed in NHL. We therefore analyzed the involvement of aberrations of these pathways in NHLs from the population-based West-Danish NHL registry, LYFO registry, as well as in a series of neurofibromatosis 1-related tumors. The aim of the studies was to obtain information about extent and interrelation of alterations of pathway components, as well as clinical information such alterations might provide. We found that alteration of components of one or both of these pathways are very common, occurring in the vast majority of DLCLs. Our data suggest that the pathways are not entirely linear in lymphomagenesis. The p53 pathway components MDM2 and p53 were frequently altered in the same lymphoma indicating that the role of MDM2 in lymphomagenesis is not entirely dependent on the downstream target, p53. The linearity of the RB1 pathway was clearer as only 1 of 34 DLCLs showed aberration of more than one of the components cyclin D3, p16INK4A, and pRB. An intriguing novel observation was that p16INK4A inactivation was associated with increased expression of cdk4, a kinase target of p16INK4A inhibitory function. This could indicate the existence of a regulatory feedback loop between p16INK4A and cdk4. Cyclin D3 has yet to be established as an oncoprotein. Our finding of cyclin D3 overexpression in a significant number of DLCLs (including all thyroid lymphomas analyzed), as well as the intimate inverse relation to other RB1 pathway alterations suggest, that cyclin D3 is important in lymphomagenesis. However, further studies are needed to implicate cyclin D3 definitively as an oncoprotein. Our data contain several lines of evidence supporting roles of CDKN2A and MDM2 in progression of neoplastic disease. We found that loss of p16INK4A coincided with transformation of neurofibromas to malignant peripheral nerve sheath tumors in neurofibromatosis 1 patients. Furthermore, one DLCL lost CDKN2A from diagnosis to relapse. MDM2 overexpression was more frequent in aggressive than in indolent lymphomas, and in follicle center lymphomas none of our follicle center grade I/II lymphomas overexpressed MDM2. In contrast, MDM2 was overexpressed in 60% of grade III/diffuse follicle center lymphomas. Clinical correlations revealed novel and interesting findings. Both p53 disruption and low expression of E2F-1 correlated with poor response of aggressive lymphomas to treatment. Chemotherapeutic regimens used in lymphoma treatment are based on apoptosis induction, and as both E2F-1 and p53 are regulators of apoptosis, it is possible that the observed treatment failure is associated with reduced E2F-1- and p53-mediated apoptosis. Survival analyses revealed numerous novel and potentially important findings. Several of the studied cell cycle regulators carried independent prognostic value in various subsets of lymphomas. In DLCL, both p16INK4A inactivation and reduced E2F-1 expression conferred shortened survival. p53 alteration was associated with poor prognosis of both B-cell and, especially, T-cell lymphoma. Low expression of p27, a cell cycle regulator haplo-insufficient for tumor suppression, predicted poor outcome in indolent and aggressive lymphoma, and overexpression of cyclin D3 was associated with poor prognosis in indolent lymphomas. Finally, MDM2 overexpression identified among patients with follicle center lymphomas, extranodal marginal zone lymphomas, and mantle cell lymphomas cases with poor prognosis. While these results must necessarily be confirmed on larger prospective series of patients, the data nonetheless suggest that valuable prognostic information can be provided by studies of these cell cycle regulators.
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PMID:Molecular control of the cell cycle in cancer: biological and clinical aspects. 1281 37

We present six cases of a plexiform nerve sheath tumor of childhood that previously had been designated a form of malignant peripheral nerve sheath tumor (MPNST), and we provide evidence that such tumors are in fact benign plexiform cellular schwannomas. At presentation, the four girls and two boys ranged in age from 2 to 15 months with tumors of the leg (four), deep groin and upper thigh (one), and pelvis (one). Of the six lesions, five were congenital and none was associated with type 1 neurofibromatosis. Tumor sizes ranged from 2.0 to 9 cm, with three larger than 5 cm. Three tumors were well circumscribed, two were purely infiltrative, and one had a mixed circumscribed and infiltrative growth pattern. Peripheral nerve involvement was evident in two cases. Grossly, the tumors were multinodular or plexiform in configuration and, on sectioning, lobulated and homogeneously tan without necrosis. Characteristic histologic features included hypercellularity, composition of cells spindle in shape with elongate hyperchromatic nuclei, and indistinct cellular outlines. Their nuclei varied minimally in size and shape but were at least three times the size of typical neurofibroma nuclei. Mitoses were seen in every tumor and in the areas of greatest proliferative activity ranged from 4 to 31/10 high power fields. MIB-1 staining of at least 30% of the cells was noted in three cases. In five cases in which p53 immunoreactions were performed, no nuclear staining was evident. That the tumors are schwannomas was evident from their uniform strong staining for S-100 protein and an ultrastructure in all five cases showing only differentiated neoplastic Schwann cells. Architecturally, the tumors differed from conventional schwannoma and nonplexiform cellular schwannomas by their lack of both well-formed capsules and degenerative changes. Follow-up was available in all cases and ranged from 2 to 13.6 years. All tumors recurred locally and were treated by local resections. With the exception of one child lost to follow-up at 25 months, all the children are alive and free of disease. Our data combined with cases previously reported by Meis-Kindblom and Enzinger show a childhood peripheral nerve tumor unassociated with type 1 neurofibromatosis, occurring most commonly in infants, often presenting as a congenital tumor and, though prone to local recurrence, having no metastatic potential. The behavior is that of a benign tumor, although its often rapid growth, hypercellularity and increased mitotic activity, sometimes locally aggressive behavior, and difficulties encountered in obtaining tumor-free margins are unsettling to pathologist and clinician alike. These features may lead to a misdiagnosis of malignancy, which could result in harmful overtreatment.
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PMID:Congenital and childhood plexiform (multinodular) cellular schwannoma: a troublesome mimic of malignant peripheral nerve sheath tumor. 1450 93

The stability of p53 tumor suppressor is regulated by Mdm2 via the ubiquitination and proteasome-mediated proteolysis pathway. The c-Abl and PTEN tumor suppressors are known to stabilize p53 by blocking the Mdm2-mediated p53 degradation. This study investigated the correlation between p53 and merlin, a neurofibromatosis 2 (NF2)-related tumor suppressor, in association with the Mdm2 function. The results showed that merlin increased the p53 stability by inhibiting the Mdm2-mediated degradation of p53, which accompanied the increase in the p53-dependent transcriptional activity. The stabilization of p53 by merlin appeared to be accomplished through Mdm2 degradation, and the N-terminal region of merlin was responsible for this novel activity. This study also showed that overexpression of merlin-induced apoptosis of cells depending preferentially on p53 in response to the serum starvation or a chemotherapeutic agent. These results suggest that merlin could be a positive regulator of p53 in terms of tumor suppressor activity, and provide the promising therapeutic means for treating tumors with non-functional merlin or Mdm2 overexpression.
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PMID:Merlin neutralizes the inhibitory effect of Mdm2 on p53. 1467 3

The human polyomavirus, JC virus, has recently been associated with several human CNS tumors, including medulloblastomas and a broad range of glial-origin tumors. This ubiquitous virus is the causative agent of the rare demyelinating disease, progressive multifocal leukoencephalopathy in immunocompromised individuals. Expression of the viral protein, T-antigen, which possesses the ability to transform cells of neural origin, has been detected in human CNS tumors. In an effort to further understand the transforming potential of JCV T-antigen, transgenic mice expressing JCV T-antigen under the control of the Mad-4 promoter were generated. As described previously, approximately 50% of the animals developed pituitary tumors by 1 year of age. However, a small subset of the animals developed solid masses arising from the soft tissues surrounding the salivary gland, the sciatic nerve, and along the extremities that histologically resemble malignant peripheral nerve sheath tumors, rare neoplasms that occur in individuals with neurofibromatosis type 1 (NF1). JCV T-antigen was detected in tumor tissue by immunohistochemistry and immunoprecipitation/Western blotting, but not in normal tissues and was colocalized with NF2, the putative tumor suppressor protein associated with neurofibromatosis type 2, in the nucleus of some cells. In addition, T-antigen was co-precipitated with NF2, but not with NF1 protein, although NF1 was detectable in tumor tissue. Furthermore, precipitated immunocomplexes contained T-antigen, NF2, and p53, suggesting that these three proteins may form a ternary complex. The importance of these findings on mechanisms of T-antigen-mediated tumorigenesis and the pathogenesis of neurofibromatosis are discussed. Oncogene (2004) 23, 5459-5467. doi:10.1038/sj.onc.1207728 Published online 10 May 2004
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PMID:JCV T-antigen interacts with the neurofibromatosis type 2 gene product in a transgenic mouse model of malignant peripheral nerve sheath tumors. 1513 94

The ovarian corpus luteum plays a critical role in reproduction being the primary source of circulating progesterone. After ovulation the corpus luteum is build by avascular granulosa lutein cells through rapid vascularization regulated by gonadotropic hormones. The present study was performed to investigate whether this process might be influenced by the human chorionic gonadotropin (hCG)-dependent expression of different tumor suppressor genes and hypoxia dependent transcription factors. RNA was isolated from cultured granulosa lutein cells, transcribed into cDNA, and the transcript level of following genes were determined: RB-1, VHL, NF-1, NF-2, Wt-1, p53, APC, and hypoxia inducible factor-1 (HIF-1), -2, and -3alpha. Additionally, the influence of hCG on the expression of VHL, p53, and HIf2alpha were investigated. We demonstrate that in human granulosa lutein cells the tumor suppressor genes RB-1, VHL, NF-1, NF-2, Wt-1, p53, and APC and the hypoxia dependent transcription factors HIF-1alpha, -2alpha, and -3alpha are expressed. In addition, we showed that hCG regulates the expression of p53, VHL, and HIF-2alpha. Our results indicate that hCG may determine the growth and development of the corpus luteum by mediating hypoxic and apoptotic pathways in human granulosa lutein cells.
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PMID:Chorionic gonadotropin regulates the transcript level of VHL, p53, and HIF-2alpha in human granulosa lutein cells. 1545 16


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