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)

UVB irradiation is known to produce DNA damage at mutation hotspots in the p53 tumor suppressor gene, leading to the development of skin cancers. Mutations in the PTCH tumor suppressor gene, which is known to be responsible for the development of nevoid basal cell carcinoma syndrome, have also been identified in sporadic basal cell carcinomas (BCCs). We describe the case of an 80-year-old welder in whom 3 novel p53 mutations, as well as UV-specific PTCH mutations, were detected in two BCC samples from sun-exposed skin. The simultaneous presence of UV-specific p53 and PTCH mutations in the same BCC sample has not previously been reported.
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PMID:UV-specific p53 and PTCH mutations in sporadic basal cell carcinoma of sun-exposed skin. 1117 90

Mutations of p53 and PTCH gene, two candidate tumor suppressor genes for basal cell carcinoma (BCC), were screened in 15 cases of sporadic BCCs that developed in sun-exposed skin region in a Korean population. p53 and PTCH mutations were detected at a frequency of 33 and 40%, respectively, and the mutations were predominantly UV-signature transition, C-->T transitions at dipyrimidine sites and CC-->TT tandem mutations. In both genes, the most common mutations were missense mutations resulting in amino acid substitution, which is different than the results from Caucasian BCCs where mutations are frequently predicted to make truncated or absent proteins. All mutations, except for one, occurred on the nontranscribed strand where is little efficient removal of UV-induced pyrimidine dimers relative to the transcribed strand. Loss of heterozygocity (LOH) of 9q22 for PTCH loci was found in eight of 15 informative cases of BCCs (53%), but none of the cases were informative for LOH of 17p13 for p53 loci. Not only do our data indicate the key role played by p53 and PTCH in the development of BCCs, these findings also suggest that UVB may significantly contribute to BCC tumorigenesis. Moreover, molecular epidemiology composed of incidence of p53 and PTCH mutations, difference in the type of mutation and repair bias of UV-induced DNA lesions might affect the distinct features of BCCs between different racial population.
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PMID:Mutations of the p53 and PTCH gene in basal cell carcinomas: UV mutation signature and strand bias. 1200 15

Immunocytochemical studies of the expression of PCNA, Ki67 and p53 protein have been done by different groups on sporadic keratocysts (OKCs) and OKCs associated with the naevoid basal cell carcinoma syndrome (NBCCS). These 'markers' have in common that they are all expressed in actively proliferating cells, particularly in neoplasms. The findings were compared with their expression in dentigerous and radicular cysts. While there was some variability in the reported results, probably because of technical inconsistencies and the use of different antibodies, a definite trend emerged. In general PCNA, Ki67 and p53 positivity occurred more frequently and more intensely in the OKCs, and in the syndrome-related more than the solitary, compared with the other cyst types. In the OKCs the positivity was expressed mostly in the suprabasal layers of epithelium whereas in the other cysts types it was mainly in the basal layer that positivity was observed. Other studies showed that the gene for the NBCCS (PTCH), a tumour suppressor gene, mapped to chromosome 9q22.3. PTCH gene mutation has been shown to be an important step in the pathogenesis of the OKC and was thought to have a role in the development of the sporadic as well as the syndrome-related OKCs. The 'two-hits' hypothesis was invoked in support of the view that syndrome-related basal cell carcinomas (BCCs) and OKCs probably arise from precursor cells that contain an inherited 'first hit'. Only a single mutation was then required in the somatic cell to cause homozygous inactivation and neoplastic progression. Sporadic OKCs might arise from susceptible cells in which two somatic mutations or 'hits' have occurred, one of which manifests as allelic loss. The loss of tumour suppressor genes supports the view that the OKC is a benign neoplasm.
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PMID:The aggressive nature of the odontogenic keratocyst: is it a benign cystic neoplasm? Part 2. Proliferation and genetic studies. 1207 94

Recent research is revealing combinations of disturbed oncogenic and tumor-suppressive signaling pathways by altered or missing genes in skin cancers: mutated PTCH (in the mitogenic Sonic Hedgehog pathway) and mutated p53 tumor suppressor gene in basal cell carcinomas (BCC), possibly an activated mitogenic RAS pathway and mutated p53 in squamous cell carcinomas (SCC), and possibly an activated MET/RAS pathway and inactive p16(INK4a) tumor suppressor in cutaneous melanomas. UV radiation damages DNA and can give rise to genomic alterations, varying from point mutations to crude chromosomal dislocations. UVB radiation (wavelength band 280-315 nm) is more carcinogenic than UVA radiation (315-400 nm) in experimental induction of SCC. The impact of UVB radiation can be clearly inferred from the characteristic point mutations in p53 found in human SCC and BCC. In contrast to UVB radiation, much of the mutagenic and carcinogenic action of UVA radiation appears to be mediated through reactive oxygen species (ROS). Experiments have shown that UVA1 (340-400 nm) exposure induces SCC largely without the characteristic point mutations in p53. Both UVB and UVA radiation can give rise to ROS-related point mutations (e.g. G to T) and crude genomic alterations (e.g. deletions) which may not be recognized as caused by UV radiation.
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PMID:Photocarcinogenesis: UVA vs. UVB radiation. 1223 25

Bladder cancer is the most common urinary tumors in China. Carcinogenesis of bladder is a multistep process. Accumulation of abnormal genotypes in a long period leads to malignant phenotypes. The genes associated with bladder carcinogenesis include oncogenes (such as H-ras, FGFR3, erbB2, CCND1, mdm2), tumor suppressor genes (such as INK4A/ARF, Rb, TP53, PTEN, TSC1, PTCH, DBCCR1), and DNA mismatch repair genes, etc. In this review, the authors discussed the recent research advances on the genes associated with bladder carcinoma.
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PMID:[Research advances on bladder cancer associated genes]. 1256 47

The UVB component of the solar spectrum induces DNA lesions that, in the absence of error-free DNA repair, may give rise during DNA replication to mutations in caretaker and gatekeeper genes. The DNA repair genes are the best candidates for caretaker genes as exemplified by the human hereditary xeroderma pigmentosum (XP) syndrome. Cultured XP cells are hypermutable after UVB irradiation. This increased mutation frequency is also found in gatekeeper genes, which govern signalling pathways implicated in the control of cellular proliferation, differentiation and survival of human epidermal keratinocytes. We describe and discuss the role of mutated gatekeeper genes in five specific signalling pathways which have been implicated in skin carcinogenesis. The pathways we focus on in this review are: (i) P16(INK4A)-CDK4/6-RB; (ii) P14(ARF)-HDM2-P53; (iii) Sonic hedgehog (SHH)/GLI; (iv) WNT/beta-catenin; and (v) Bone Morphogenetic Protein (BMP)/SMAD. 70-80% of XP skin cancers exhibit one or several mutations in the P53, PTCH-1, SMO or CDKN2A genes, the type and frequency of mutated genes being different between squamous cell (SCCs) and basal cell carcinomas (BCCs). In XP cancers, the typically UVB-induced CC to TT tandem transitions represent approximately 60% of total mutations compared to 10-15% in skin tumours from DNA repair-proficient patients. Acquired activation of the pathways described herein can alter proliferation and differentiation of keratinocytes, allowing a damaged cell to replicate and give rise to mutated daughter cells, then eventually to the development of the carcinogenic process following clonal selection.
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PMID:UVB-induced mutations in human key gatekeeper genes governing signalling pathways and consequences for skin tumourigenesis. 1452 Dec 17

Basal cell carcinomas and squamous cell carcinomas are the most common human cancers and increasing in incidence. The development of novel, pathogenesis-based therapies requires a better knowledge of the molecular mechanisms leading to the development of these tumors. Basal cell carcinomas are characterized by aberrant activation of Sonic-Hedgehog (SHH) signaling due to mutations in the PTCH or SMOH genes. In addition, about 50% of the cases carry mutations in the TP53 tumor suppressor gene. Squamous cell carcinomas lack alterations of SHH signaling, while TP53 mutations are detectable in virtually all cases. Alterations in cell cycle regulatory genes, such as CDKN2A, are also common. Recently, specific inhibitors of the SHH-signaling pathway have been developed and shown promising results in preclinical studies on experimental basal cell carcinomas. However, the clinical significance of such targeted molecular therapy remains to be evaluated. Another successful pathogenesis-based therapy, which is already in clinical use, is the administration of topic immune response modifier imiquimod. This drug can eradicate non-melanoma skin cancers by different mechanisms, including cytokine-mediated stimulation of the anti-tumor immune response, as well as the induction of tumor cell apoptosis.
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PMID:[Cutaneous epithelial tumors. Molecular biology and pathogenesis-based therapy]. 1463 45

Cerebellar liponeurocytoma, a rare, newly identified CNS neoplasm of adults, is characterized by advanced neuronal/neurocytic and focal lipomatous differentiation, low proliferative potential and a favorable clinical prognosis. Despite the different age distribution and benign biological behavior, the cerebellar liponeurocytoma shares several features with the cerebellar medulloblastoma, which may include an origin from the periventricular matrix of the fourth ventricle or the external granular layer of the cerebellum. To establish the genetic profile of cerebellar liponeurocytomas, we have formed an international consortium and collected tumor samples from 20 patients. DNA sequencing revealed TP53 missense mutations in 4 (20%) of 20 cerebellar liponeurocytomas, a frequency higher than in medulloblastomas. There was no case with PTCH, APC, or beta-catenin mutations, each of which may be present in subsets of medulloblastomas. Isochromosome 17q, a genetic hallmark of classic medulloblastomas, was not observed in any of the cases investigated by FISH analysis. cDNA array analyses were carried out on 4 cerebellar liponeurocytomas, 4 central neurocytomas, and 4 classic medulloblastomas. Cluster analysis of the cDNA expression data of 1176 genes grouped cerebellar liponeurocytomas close to central neurocytomas, but distinct from medulloblastomas. These results suggest cerebellar liponeurocytoma as a distinct tumor entity that is genetically different from medulloblastoma. Furthermore, the cDNA expression array data suggest a relationship to central neurocytomas, but the presence of TP53 mutations, which are absent in central neurocytomas, suggests that their genetic pathways are different.
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PMID:Genetic and expression profiles of cerebellar liponeurocytomas. 1544 83

Embryonal tumors, the most common group of malignant brain tumors in childhood, are heterogeneous and have been associated with a large number of genetic abnormalities. The aim of this study was to comprehensively analyze loss of heterozygosity (LOH) on regions harboring suppressor genes (PTCH2, PTCH1, APC, PTEN, DMBT1, SUFU, AXIN1, hSNF5/INI1) and to study chromosomal regions in which deletions have been described most frequently (1p, 1q, 11p, 16p, 17p). Twenty-nine children (17 male and 12 female), aged from 1 year 13 years were included in this study. There were 24 medulloblastomas (MB) and 5 supratentorial primitive neuroectodermal tumors (sPNET). Tissue samples from 29 primary and 11 recurrent tumors were analyzed according to the LOH standard procedures, which were extended to include fluorescence in situ hybridization for detection of isochromosome 17q (i(17q)) and direct sequencing ofTP53 exon 4. LOH on 17p was found in 15 out of 29 tumors. FISH analysis identified the presence of i(17q) in 16 tumors. Comparison of LOH analysis and the FISH data indicated that alterations of 17p were related to be the introduction of an i(17q) formation. LOH on 10q and 9q was observed in 4 and 2 cases, respectively, and was associated with alterations of chromosome 17. These results indicated a connection between alterations of PTCH/SHH genes and abnormalities of chromosome 17. A deleted region on 22q, covering the hSNF5/INI1 locus, was observed in 3 tumors. Progression of the molecular changes occurred in 1 case of recurrent medulloblastoma. LOH on 10q and 17p was found in both primary and recurrent tumor, while losses on 11p, 16p, and 16q occurred only in the recurrent tumor. No evidence of alteration in TP53 exon 4 was identified.
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PMID:Molecular abnormalities in pediatric embryonal brain tumors--analysis of loss of heterozygosity on chromosomes 1, 5, 9, 10, 11, 16, 17 and 22. 1558 Oct 23

Every living organism on the surface of the earth is exposed to the ultraviolet (UV) fraction of the sunlight. This electromagnetic energy has both life-giving and life-endangering effects. UV radiation can damage DNA and thus mutagenize several genes involved in the development of the skin cancer. The presence of typical signature of UV-induced mutations on these genes indicates that the ultraviolet-B part of sunlight is responsible for the evolution of cutaneous carcinogenesis. During this process, variable alterations of the oncogenic, tumor-suppressive, and cell-cycle control signaling pathways occur. These pathways include (a) mutated PTCH (in the mitogenic Sonic Hedgehog pathway) and mutated p53 tumor-suppressor gene in basal cell carcinomas, (b) an activated mitogenic ras pathway and mutated p53 in squamous cell carcinomas, and (c) an activated ras pathway, inactive p16, and p53 tumor suppressors in melanomas. This review presents background information about the skin optics, UV radiation, and molecular events involved in photocarcinogenesis.
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PMID:Ultraviolet radiation and skin cancer: molecular mechanisms. 1570 Oct 81


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