Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: UNIPROT:P04637 (p53)
77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The molecular biology underlying the development of highly malignant peripheral nerve sheath tumors (MPNSTs) remains mostly unknown. In the present study, the expression pattern of 10 selected cell cycle components is investigated in a series of 15 MPNSTs from patients with (n = 9) or without (n = 5) neurofibromatosis type 1 (NF1). Thirteen tumors did not express the cyclin-dependent kinase inhibitor, p16(INK4A), an observation that was related to homozygote gene deletions in three tumors, heterozygote deletions in five, and gross gene rearrangements in five. The absence of protein expression in the tumors with one seemingly intact allele was not caused by promoter hypermethylation of p16(INK4A) or p14(ARF). All tumor samples expressed normal sized RB1, cyclin D3, CDK2, CDK4, p21(CIP1), and p27(KlP1) proteins, and only a single tumor showed an aberrant protein band for one of these proteins, p21(CIP1). Cyclin D1 was absent in four tumors; all except one tumor showed expression of TP53 protein, and three of nine MPNSTs had expression of normal-sized MDM2. In conclusion, this study shows that the vast majority of MPNSTs had gross rearrangements of the p16(INK4A) gene, explaining the absence of the encoded protein in the same tumors. The level of expression was equally distributed between the familial (NF1) and sporadic cases, although it should be noted that the 2 cases with p16(INK4A) expression were sporadic. The data imply that the complete absence of p16(INK4A) is sufficient for activation of the cell cycle in most MPNSTs; thus, it is not necessary for tumor proliferation to further stimulate the cycle through alteration of other central components.
...
PMID:Expression patterns of cell cycle components in sporadic and neurofibromatosis type 1-related malignant peripheral nerve sheath tumors. 1571 87

Recent advances in the molecular genetic of adrenal tumors give new insights in the pathophysiology of these neoplasms in both hereditary and sporadic cases. The practice of genetic counselling in patients with adrenal tumors have been recently changed by the identification and the understanding of new specific hereditary cancer susceptibility syndromes. In the case of sporadic adrenocortical tumors these progress also offer new prognosis predictors. The genetic predisposition to adrenocortical cancer in children has been well established in the Li-Fraumeni and Beckewith-Wiedeman syndromes due to germline p53 mutation located at 17p13 and dysregulation of the imprinted IGF-2 locus at 11p15, respectively. Adrenocortical tumors are also observed in Multiple Endocrine Neoplasia type I syndrome. Cushing's syndrome due to primary pigmented nodular adrenocortical disease have been observed in patients with germline PRKAR1A inactivating mutations. Interestingly allelic loss at 17p13 and 11p15 have been observed in sporadic adrenocortical cancer and somatic PRKAR1A mutations in secreting adrenocortical adenomas. The potential interest of these finding for the diagnosis of these tumors will be discussed. In the case of pheochromocytoma and paraganglioma, the demonstration that three genes encoding three succinate dehydrogenase subunits (SDHD, SDHB, SDHC), belonging to the complex II of the respiratory chain in the mitochondria, are involved in the genetics of familial and especially in apparently sporadic phaeochromocytomas have dramatically modified our practice. Up to date, four diagnosis of familal disease (multiple endocrine neoplasia type II, von Hippel Lindau disease, neurofibromatosis type 1 and hereditary paraganglioma) should be discussed and causative mutations in six different phaechomocytoma susceptibility genes (RET, VHL, NF1, SDHB, SDHD, SDHC) could be identified. In this review, we will perform an update compiling these new clinical, genetic and functional data recently published. We will suggest guidelines for the practice of the phaeochomocytoma genetic testing in the patients and their families, and for an early detection of tumors in the patients or in individuals determined to be at-risk of disease by the presymptomatic genetic testing.
...
PMID:New insights in the genetics of adrenocortical tumors, pheochromocytomas and paragangliomas. 1600 32

Cancer is a complex disease in which cells acquire many genetic and epigenetic alterations. We have examined how three types of alterations, mutations in tumor suppressor genes, changes in an imprinted locus, and polymorphic loci, interact to affect tumor susceptibility in a mouse model of neurofibromatosis type 1 (NF1). Mutations in tumor suppressor genes such as TP53 and in oncogenes such as KRAS have major effects on tumorigenesis due to the central roles of these genes in cell proliferation and cell survival. Imprinted genes expressed from only one parental chromosome affect tumorigenesis if their monoallelic expression is lost or duplicated. Because imprinted loci are within regions deleted or amplified in cancer, the parental origin of genomic rearrangements could affect tumorigenesis. Gene polymorphisms can vary tumor incidence by affecting rate-limiting steps in tumorigenesis within tumor cells or surrounding stroma. In our mouse model of NF1, the incidence of tumors mutant for the tumor suppressor genes Nf1 and Trp53 is strongly modified by a linked imprinted locus acting epistatically on two unlinked polymorphic loci, Nstr1 and Nstr2. This interaction of an imprinted locus and polymorphic susceptibility loci has profound implications for human mapping studies where the parental contribution of alleles is often unknown.
...
PMID:An imprinted locus epistatically influences Nstr1 and Nstr2 to control resistance to nerve sheath tumors in a neurofibromatosis type 1 mouse model. 1639 17

We describe a girl with neurofibromatosis type 1 (NF1), mild dysmorphic features, growth and mental retardation, autism, and mosaicism of ring chromosome 17 and chromosome 17 monosomy. The extent of genetic material deleted from the ring chromosome was determined using a combination of classical cytogenetics, fluorescence in situ hybridization (FISH) and multiplex ligation-dependent probe amplification (MLPA) to be 0.6-2.5 Mb on 17p, and up to about 10 Mb on 17q. Based on our observations and on a review of the literature we argue that in addition to a universal "ring syndrome" which is based on ring instability and is less specific for the chromosome involved, various ring chromosomes underlie their own characteristic phenotypes. We propose that the symptoms leading to the diagnosis of NF1 in our patient could be attributed to mosaic hemizygosity for the NF1 gene in some of her somatic cells. A similar mechanism or a direct involvement of respective disease genes in the aberration could possibly influence also the development of autism and other symptoms. We raise a question if the loss of one copy of chromosome 17 from a substantial fraction of somatic cells can have specific consequences also for future risks of the patient, for example, due to the mosaic hemizygosity for the BRCA1 and TP53 genes.
...
PMID:A girl with neurofibromatosis type 1, atypical autism and mosaic ring chromosome 17. 1716 20

The author reviewed five hereditary neurological tumor syndromes associated with gliomas: Li-Fraumeni cancer syndrome, neurofibromatosis type 1 (NF1) and type 2 (NF2), tuberous sclerosis (TS), and Turcot syndrome. In each case, clinical manifestation, genetic localization, and protein function were identified. Correlation with glioma oncogenesis demonstrated the following associations: 1) p53 mutation (Li-Fraumeni) with astrocytoma progression; 2) NF1 mutation (NF1) with pilocytic astrocytomas; and 3) NF2 mutation (NF2) with ependymoma formation. The role of the TS gene and the adenomatous polypopsis coli gene (Turcot syndrome) in glioma oncogenesis is not clear. Because tumorigenesis is a multistep process, it would be premature to equate a specific germline mutation with the multiple somatic mutations required for glioma formation. However, identification of specific germline genetic mutations provides a model for the multiple tumor suppressor genes involved in glioma pathogenesis.
...
PMID:Hereditary neurological tumor syndromes: clues to glioma oncogenesis? 1716 1

Defects in genes that control DNA repair, proliferation, and apoptosis can increase genomic instability, and thus promote malignant progression. Although most tumors that arise in humans with neurofibromatosis type 1 (NF1) are benign, these individuals are at increased risk for malignant peripheral nerve sheath tumors (MPNST). To characterize additional mutations required for the development of MPNST from benign plexiform neurofibromas, we generated a mouse model for these tumors by combining targeted null mutations in Nf1 and p53, in cis. CisNf1+/-; p53+/- mice spontaneously develop PNST, and these tumors exhibit loss-of-heterozygosity at both the Nf1 and p53 loci. Because p53 has well-characterized roles in the DNA damage response, DNA repair, and apoptosis, and because DNA repair genes have been proposed to act as modifiers in NF1, we used the cisNf1+/-; p53+/- mice to determine whether a mutator phenotype arises in NF1-associated malignancies. To quantitate spontaneous mutant frequencies (MF), we crossed the Big Blue mouse, which harbors a lacI transgene, to the cisNf1+/-; p53+/- mice, and isolated genomic DNA from both tumor and normal tissues in compound heterozygotes and wild-type siblings. Many of the PNST exhibited increased mutant frequencies (MF=4.70) when compared to normal peripheral nerve and brain (MF=2.09); mutations occurred throughout the entire lacI gene, and included base substitutions, insertions, and deletions. Moreover, the brains, spleens, and livers of these cisNf1+/-; p53+/- animals exhibited increased mutant frequencies when compared to tissues from wild-type littermates. We conclude that a mild mutator phenotype arises in the tumors and tissues of cisNf1+/-; p53+/- mice, and propose that genomic instability influences NF1 tumor progression and disease severity.
...
PMID:A mild mutator phenotype arises in a mouse model for malignancies associated with neurofibromatosis type 1. 1720 58

Malignant peripheral nerve sheath tumors (MPNST) are sarcomas with poor prognosis and limited treatment options. Factors contributing to tumor progression are largely unknown. We therefore examined MPNST from 22 neurofibromatosis type 1 (NF1) patients, 14 non-NF1 patients, and 14 neurofibroma patients for matrix metalloproteinase 13 (MMP-13) expression. Because wild-type and mutant p53 were shown to differentially regulate MMP-13 expression, TP53 status and protein levels were also determined. MMP-13 expression was detected in 58% of MPNST and was significantly associated with recurrent MPNST (P = .019). p53 was observed in 78% of MPNST and was found to be strongly associated with MMP-13 expression (P = .005). In contrast, 14 neurofibromas lacked MMP-13 and p53 expressions. TP53 mutations were found in only 11% of MPNST and were associated with high tumor grades (P = .029). No significant association between mutant TP53 and MMP-13 was observed, indicating that other factors drive MMP-13 expression in MPNST. The presence of metastasis was linked to p53Pro(72) polymorphism (P = .041) and shorter survival. In summary, our data suggest that MMP-13 expression in nerve sheath tumors is coupled with malignant progression. Therefore, MMP-13 may serve as a marker for progression and as a therapeutic target.
...
PMID:MMP-13 and p53 in the progression of malignant peripheral nerve sheath tumors. 1778 86

About 10% of neurofibromatosis type 1 (NF1) patients develop malignant peripheral nerve sheath tumors (MPNSTs) and represent considerable patient morbidity and mortality. Elucidation of the genetic mechanisms by which inherited and acquired NF1 disease gene variants lead to MPNST development is important. A study was undertaken to identify the constitutional and somatic NF1 mutations in 34 MPNSTs from 27 NF1 patients. The NF1 germline mutations identified in 22 lymphocytes DNA from these patients included seven novel mutations and a large 1.4-Mb deletion. The NF1 germline mutation spectrum was similar to that previously identified in adult NF1 patients without MPNST. Somatic NF1 mutations were identified in tumor DNA from 31 out of 34 MPNSTs, of which 28 were large genomic deletions. The high prevalence (>90%) of such deletions in MPNST contrast with the =or<20% found in benign neurofibromas and is indicative of the involvement of different mutational mechanisms in these tumors. Coinactivation of the TP53 gene by deletion, or by point mutation along with NF1 gene inactivation, is known to exacerbate disease symptoms in NF1, therefore TP53 gene inactivation was screened. DNA from 20 tumors showed evidence for loss of heterozygosity (LOH) across the TP53 region in 11 samples, with novel TP53 point mutations in four tumors.
...
PMID:Germline and somatic NF1 gene mutation spectrum in NF1-associated malignant peripheral nerve sheath tumors (MPNSTs). 1796 Jul 68

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.
...
PMID:Syndromic and sporadic pediatric optic pathway gliomas: review of clinical and histopathological differences and treatment implications. 1800 65

Neurofibromatosis type 1 (NF1) is an autosomal dominant condition with a birth incidence of 1/3,500. Around 50% of cases are due to new mutations. The NF1 gene maps to 17q11.2 and encodes neurofibromin. NF1 is a "classical" tumor suppressor gene. Congenital disseminated NF1 is rare with just two cases previously reported. We present a deceased baby with congenital disseminated NF1 in whom we performed molecular studies. A germline mutation (R461X) in exon 10a of the NF1 gene was found. A 2 bp deletion (3508delCA) in codon 1170 of exon 21 was identified in DNA derived from some tumor tissue. Loss of heterozygosity in NF1 and TP53 was observed in other tumor samples. No microsatellite instability was observed in the tumor samples. This is the first report of molecular analysis of the NF1 locus in a patient with disseminated congenital neurofibromatosis. This case had a de novo germline mutation in NF1 and three documented somatic mutations in the NF1 and TP53 genes in tumor specimens.
...
PMID:Congenital disseminated neurofibromatosis type 1: a clinical and molecular case report. 1843 96


<< Previous 1 2 3 4 5 6 7 8 9 Next >>

---