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)

Epidemiological studies on intracranial tumors have suggested that the observed familial aggregation of a proportion of gliomas may be due to inherited predisposition to their development. In the Li-Fraumeni syndrome (LFS) associated with germ-line mutations of the p53 gene, nervous-system tumors are observed with increased frequency. However, the contribution of germ-line p53 mutation to the incidence of brain tumors has not been investigated. In order to address this point, we have performed 2 independent investigations. First, we have examined an unselected series of brain tumors. Whenever the presence of a p53 mutation in the tumor was observed, the possible germ-line origin of the mutation was investigated. Germ-line p53 mutations were also analyzed in constitutional DNA of patients with gliomas that had been selected for an unusual personal or familial history of cancer. Germ-line p53 mutations were detected in 1 out of 80 unselected cases and in 3 out of 15 selected cases (20%). We conclude that germ-line p53 mutation may contribute to a small fraction of gliomas that develop in the general population. The presence of a personal or familial history of cancer in a patient with glioma should prompt the search for a germ-line p53 mutation. However, the low frequency of p53 germ-line mutation suggests that alterations of this gene may not account for most familial cases of gliomas.
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PMID:Incidence of germ-line p53 mutations in patients with gliomas. 855 Feb 39

The formation of human malignant gliomas is thought to involve the accumulation of multiple genetic alterations. To define the function of specific alterations in glioma formation, we serially introduced genetic alterations functionally equivalent to those noted in human malignant gliomas into normal human astrocytes (NHAs). We then monitored the ability of each of these alterations to contribute to the growth of otherwise genetically stable NHAs into intracranial malignant gliomas. Using this model, we show that expression of human telomerase catalytic component (hTERT), but not E7-mediated inactivation of pRb or E6/E7-mediated inactivation of p53/pRb, was sufficient to initiate the tumorigenic process by circumventing cellular senescence in astrocytes. hTERT expression, even in combination with inactivation of p53/pRb, did not transform astrocytes. These alterations together, however, cooperated with ras pathway activation (initiated by expression of mutant H-Ras), but not with phosphatidylinositol 3-kinase pathway activation (initiated by expression of myristoylated Akt) or epidermal growth factor receptor activation, to allow for the formation of intracranial tumors strongly resembling p53/pRb pathway-deficient, telomerase-positive, ras-activated human grade III anaplastic astrocytomas. These results identify four pathways as key in the development of human anaplastic astrocytomas.
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PMID:Formation of intracranial tumors by genetically modified human astrocytes defines four pathways critical in the development of human anaplastic astrocytoma. 1143 23

Human malignant gliomas are thought to develop as the result of stepwise accumulations of multiple genetic alterations. Recently, we showed that E6/E7-mediated inactivation of p53/pRb, ras pathway activation (initiated by expression of mutant H-Ras), and expression of human telomerase reverse transcriptase (hTERT) in combination converted normal human astrocytes into cells that formed intracranial tumors resembling human anaplastic astrocytoma (AA). In this study, we created human astrocytes that, in addition to expressing E6/E7, hTERT, and Ras, also expressed a constitutive activated form of Akt intended to mimic the Akt activation noted in grade IV glioblastoma multiforme (GBM). Although these cells grew no differently than astrocytes expressing E6, E7, and H-Ras in vitro or in the first 28 days following s.c. implantation, they ultimately formed tumors four to six times larger than those formed by the E6/E7/hTERT/Ras cells. Unlike the poorly vascularized, necrosis-free AA formed by E6/E7/hTERT/Ras cells, the tumors formed by s.c. or intracranial injection of Akt-expressing cells had large areas of necrosis surrounded by neovascularization and were consistent in appearance with grade IV human GBM. These results show that activation of the Akt pathway is sufficient to allow conversion of human AA to human GBM.
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PMID:Akt pathway activation converts anaplastic astrocytoma to glioblastoma multiforme in a human astrocyte model of glioma. 1155 33

Overexpression of p53 has been reported to play a role in the development of neoplasms of the central nervous system. Meningiomas are generally benign intracranial tumors originating from the meninges. Overexpression of the p53 protein in meningiomas and an association with histological type and recurrence has been reported. Mutation of the TP53 gene leads to a more stable p53 protein in quantities high enough for detection by immunohistochemistry. In the search for these mutations the core domain of the TP53 gene of meningiomas has been analyzed. Only a very low incidence of mutations was reported. The apparent discordance between overexpression of p53 protein and TP53 gene mutations may be explained by mutations located outside the core domain. This issue was addressed in the present study. All 11 exons of 17 meningiomas were analyzed for DNA alterations by PCR single-strand conformation polymorphism (PCR-SSCP) analysis with subsequent sequencing. PCR-SSCP analysis showed a various number of band shifts and nucleotide alterations, caused either by alterations in the flanking introns or common polymorphisms (codon 36 and 72). The allele frequencies of the polymorphisms found in this small population of tumors resemble the frequencies reported in the literature. In addition, three nucleotide changes located in introns 2, 3 and 7 were found in 11, 3 and 4, respectively, of 17 specimens. Based on this study and on reports by others we conclude that it is not very likely that TP53 mutations are involved in the etiology of meningiomas.
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PMID:TP53 mutations in human meningiomas. 1193 85

Astrocytomas are the most frequent group of intracranial tumors. Among them, glioblastoma is the most aggressive one. In this review we will describe the most common genetic abnormalities found out in astrocytomas. We will refer to the epidermal growth factor receptor (EGFR), p53, p16, PTEN and DMBT1 genes. We will also present certain genetic aspects that influence the progression to glioblastoma.
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PMID:[Molecular genetics of astrocytomas]. 1288 11

Craniopharyngiomas are intracranial tumors that usually arise in the site around the sella turcica. They are composed of distinctive sheets of epithelial cells showing adamantinomatous or squamous-papillary histologic types. Because little is known about the tumorigenesis of craniopharyngiomas, we retrieved samples from 15 tumor cases to investigate the functional significance of the p53 family of transcription factors, which are known to be expressed in various human epithelia. Immunohistochemical analysis of these cases demonstrated similar expression profiles of p53 family members in the two histologic types of the tumor; i.e., strong nuclear expression of p63 was observed in all cell layers, and moderate to intense nuclear expression of p73 was observed in the basal cell layers. In contrast to p63 and p73, the reactivity of an archetypal tumor suppressor, p53, was occasional and weak in the two histologic types. Because p63 was widely expressed in the tumors, reverse transcription-polymerase chain reaction (RT-PCR) analysis was conducted to elucidate which spliced variant of p63 was expressed. The results showed that deltaNp63, lacking a terminal transactivation domain of p63, was the dominant isoform. Together with the reported evidence that the deltaNp63 isoform is highly expressed in human squamous-cell carcinomas, these data suggest that the cellular architecture characteristic of the expression of p53 family members may be required for the histogenesis of craniopharyngiomas, where deltaNp63 has a possible role in maintaining proliferative activity of the tumor cells, like squamous-cell carcinomas in other tissues.
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PMID:Immunohistochemical analysis of the p53 family members in human craniopharyngiomas. 1475 44

Mouse glioma 261 (Gl261) cells are used frequently in experimental glioblastoma therapy; however, no detailed description of the Gl261 tumor model is available. Here we present that Gl261 cells carry point mutations in the K-ras and p53 genes. Basal major histocompatibility complex (MHC)I, but not MHCII, expression was detected in Gl261 cells. The introduction of interferon-gamma-encoding genes increased expression of both MHCI and MHCII. A low amount of B7-1 and B7-2 RNA was detected in wild-type cells, but cytokine production did not change expression levels. Gl261 cells were transduced efficiently by adenoviral vectors; the infectivity of retroviral vectors was limited. Low numbers of transplanted Gl261 cells formed both subcutaneous and intracranial tumors in C57BL/6 mice. The cells were moderately immunogenic: prevaccination of mice with irradiated tumor cells 7 days before intracranial tumor challenge prevented tumor formation in approximately 90% of mice. When vaccination was carried out on the day or 3 days after tumor challenge, no surviving animals could be found. In vitro-growing cells were radiosensitive: less than 2 Gy was required to achieve 50% cell mortality. Local tumor irradiation with 4 Gy X-rays in brain tumor-bearing mice slowed down tumor progression, but none of the mice were cured off the tumor. In conclusion, the Gl261 brain tumor model might be efficiently used to study the antitumor effects of various therapeutic modalities, but the moderate immunogenicity of the cells should be considered.
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PMID:Detailed characterization of the mouse glioma 261 tumor model for experimental glioblastoma therapy. 1673 35

Congenital intracranial tumors are rare. If such a lesion is detected before birth, it is usually an incidental finding on fetal ultrasonography. The definition of a "congenital" tumor is controversial. The authors report the case of a "definite" congenital glioblastoma multiforme (GBM) diagnosed with the aid of ultrasonography and fetal magnetic resonance (MR) imaging in the 37th week of gestation. Postnatal MR imaging revealed a massive tumor occupying the patient's left temporoparietooccipital area. Angiography was performed to assess vascularity and embolize the main feeding arteries. Surgery was performed, and the tumor was successfully excised completely. The histopathological diagnosis of the tumor was GBM. An examination of the tumor cells revealed no p53 accumulation, a high MIB-1 index (87.5%), and no staining for epidermal growth factor receptor (EGFR). Adjuvant chemotherapy was administered, and the patient is doing well at 23 months of age. Congenital GBM should be considered in the differential diagnosis in cases in which a fetal ultrasonography study or fetal MR image reveals a tumor, especially in the presence of intratumoral hemorrhage. Radical tumor removal, administration of adjuvant therapy, and biological findings (such as a lack of the overexpression of p53 and EGFR in the tumor cells) all point to a longer survival time.
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PMID:Congenital glioblastoma multiforme. Case report and review of the literature. 1718 81

Meningiomas, which originate from arachnoid cells and constitute the largest subgroup of all intracranial tumors, are generally benign, yet have the capacity to progress into a higher histological grade of malignancy associated with an increase in biological aggressivity and/or capacity to recur. To elucidate meningioma pathogenesis and malignancy, we applied a holistic and network approach analyzing cDNA and tissue microarray results. A potential pathway leading to meningioma angiogenesis, apoptosis and proliferation was evidenced as well as a regulatory network of the biomarkers including Ki-67, AR, CD34, P53, c-MYC, etc. which might support clinical research. In this potential pathway, ITGB1 could be the most important "superoncogene" playing a vital role in apoptosis and proliferation, while FOXO3A, MDM4 and MT3 are important to the malignancy process. Some genes are first reported that could explain why radiation induces meningioma and why more female than male patients are affected. Further, we present the hypothesis that HIV-Tat protein might have a close relationship with meningioma pathogenesis and malignancy.
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PMID:Holistic and network analysis of meningioma pathogenesis and malignancy. 1747 81

Optic pathway gliomas (OPGs) are the most common primary neoplasm of the optic pathway. These lesions usually present in childhood and can arise anywhere along the optic pathway; they occur more frequently in women; and they rarely undergo late progression. Management strategies after the initial diagnosis are controversial, compounded by the different behaviors exhibited by sporadic and syndromic tumors. Neurofibromatosis Type 1 (NF1), with aberrant oncogenic signaling and consequent predisposition to intracranial tumors, is the most common associated syndrome, with nearly 20% of NF1 patients developing OPGs. A comorbid NF1 diagnosis has implications for tumor location with greater predilection for optic nerve involvement, whereas chiasmal and postchiasmal lesions are more frequently seen in sporadic cases. Syndromic OPGs often exhibit more indolent behavior and lower rates of clinical progression, and the majority of these are diagnosed by routine neuroophthalmological screening. When treatment is indicated, however, the molecular abnormalities that constitute this syndrome can limit the available chemotherapy and radiotherapy options because clinicians fear secondary malignancy and cerebrovascular complications. Furthermore, radiotherapy early in life can impair an individual's intellectual development, endocrine function, and physical growth, thereby limiting the role of this modality in the treatment of this childhood lesion. Differential gene expression and histogenesis among sporadic and syndromic OPGs may account for the different tumor behaviors, but studies correlating specific genetic and proteomic changes with patient outcome are pending. Loss of heterozygosity at 10 and 17q are more common among patients with NF1, and Ki67 labeling intensity of 2-3% and low p53 labeling intensity seem prognostic of aggressive tumor behavior. Recent advances in the development of a preclinical mouse model of NF1-associated OPG will permit investigation into improved detection strategies and chemotherapeutic and radiotherapy treatment protocols.
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PMID:Syndromic and sporadic pediatric optic pathway gliomas: review of clinical and histopathological differences and treatment implications. 1800 65


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