Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In approximately 60% of sporadic meningiomas, the tumour suppressor gene NF2, located on chromosome 22q, is inactivated. Mutations in the NF2 gene have been specifically reported in transitional and fibrous, but not meningothelial, meningiomas. Since meningothelial meningiomas frequently occur in anterior parts of the skull base, the association between tumour localization, size, histological subtype and NF2 status was investigated in a group of 42 sporadic meningiomas. NF2 status was determined by LOH analysis, karyotyping and FISH. Tumour size and site were evaluated by CT scans and MRIs. A strong correlation between tumour localization in the anterior skull base and intact 22q was revealed (p=0.003). On the other hand, tumour localization at the convexity was associated with disruption of NF2 (p=0.023). Furthermore, an association between chromosome 22 status and histological subtype was observed: abnormalities of chromosome 22q were more frequent in transitional and fibrous meningiomas than in the meningothelial variant (p<0.001). Also, the meningothelial meningiomas were more often located in the anterior skull base (p<0.006). Based on these findings, it is concluded that an alternative histogenesis and genetic pathway is likely to exist for meningiomas arising in the anterior skull base.
 ...
PMID:NF2 status of meningiomas is associated with tumour localization and histology. 1143 70

The current mainstream in cancer research favours the idea that malignant tumour initiation is the result of a genetic mutation. Tumour development and progression is then explained as a sort of micro-evolutionary process, whereby an initial genetic alteration leads to abnormal proliferation of a single cell that leads to a population of clonally derived cells. It is widely claimed that tumour progression is driven by natural selection, based on the assumption that the initial tumour cells acquire some properties that endow such cells with a selective advantage over the normal cells from which the tumour cells are derived. The standard view assumes that the transformed bodily cell somehow acquires "responsiveness" to natural selection independently of the whole organism to which the cell belongs. Yet, it is never explained where such an acquired capacity to respond to natural selection by the individual bodily cell comes from. This situation poses many difficult questions that so far have been left unanswered. For example, there is no explanation why some cells belonging to an organised whole and as such having no independent capacity for survival, apparently become 'independent' entities, able to respond to selective pressures in an autonomous fashion and then to be evaluated by natural selection. Hereunder it is argued that such a qualitative change cannot be the consequence of specific genetic mutations. Moreover, it is shown that natural selection is unlikely to be acting within the organism during tumour development and progression and that tumour evolution is a random, non-adaptive process, driven by no fundamental biological principle. Thus, mutations in the so-called oncogenes and tumour suppressor genes observed in epithelial cancers (that constitute more than 90% of all cancers) are not the result of selection for better cellular growth or survival under restrictive conditions. Instead, here it is suggested that they are the consequence of genetic drift acting upon gene functions that become non-relevant, either for the individual or the species fitness, once the organism is past its reproductive prime and as such, they also become superfluous for cell survival in the short term. It is proposed that the origin of cancer is epigenetic and it is a consequence of the need for a continued turnover of the individuals that constitute a species.
 ...
PMID:Cancer development and progression: a non-adaptive process driven by genetic drift. 1145 Aug 10

The development of cancer involves the accumulation of genetic changes. Over the past decade there has a been spectacular advance in the knowledge of the genetic basis of cancer, mainly as a result of the rapid progression of molecular technology. Pancreatic cancer is one of the most lethal cancers. Conventional therapeutic approaches have not had much impact on the course of this aggressive neoplasm. Knowledge of the molecular biology of pancreatic cancer has grown rapidly. Genetic alterations in pancreatic cancer include oncogene mutations (most commonly K-ras mutations), and tumour suppressor gene alterations (mainly p53, p16, DCC, etc.). These advances have potential implications for the management of this deadly disease. Identification of a hereditary genetic predisposition to pancreatic cancer has led to the formation of pancreatic cancer registries around the world, with voluntary screening of patients and siblings for the hereditary genetic defect. Asymptomatic population screening remains unrealistic, but the recognition of subpopulations at increased risk from pancreatic cancer, along with novel and sensitive detection techniques, means that targeted population screening is a step closer. Intensive research is performed in specialist laboratories to improve the diagnostic approach in patients with pancreatic cancer. The use of such molecular diagnostic methods is likely to expand. Molecular biology may also have a great impact on the treatment of pancreatic cancer, and many therapeutic approaches are being evaluated in clinical trials, including gene replacement therapy, genetic prodrug activation therapy, antisense immunology and peptide technology. The 'molecular age' has the promise of delivering still better results. This review summarises recent data relating to the molecular biology of pancreatic cancer, with emphasis on features that may be of clinical significance for diagnosis and/or therapy.
 ...
PMID:Molecular biology of pancreatic cancer: potential clinical implications. 1152 Feb 55

Statistics rate colorectal adenocarcinoma as the most common cause of cancer death on exclusion of smoking-related neoplasia. However, the reported accumulation of genetic lesions over the adenoma to adenocarcinoma sequence cannot wholly account for the neoplastic phenotype. Recently, heritable, epigenetic changes in DNA methylation, in association with a repressive chromatin structure, have been identified as critical determinants of tumour progression. Indeed, the transcriptional silencing of both established and novel tumour suppressor genes has been attributed to the aberrant cytosine methylation of promoter-region CpG islands. This review aims to set these epigenetic changes within the context of the colorectal adenoma to adenocarcinoma sequence. The role of cytosine methylation in physiological and pathological gene silencing is discussed and the events behind aberrant cytosine methylation in ageing and cancer are appraised. Emphasis is placed on the interrelationships between epigenetic and genetic lesions and the manner in which they cooperate to define a CpG island methylator phenotype at an early stage in tumourigenesis. Finally, the applications of epigenetics to molecular pathology and patient diagnosis and treatment are reviewed.
 ...
PMID:Methylation and colorectal cancer. 1156 97

Deletions of chromosome 3p are frequent in many types of neoplasia including neural crest tumours such as neuroblastoma (NB) and phaeochromocytoma. Recently we isolated several candidate tumour suppressor genes (TSGs) from a 120 kb critical interval at 3p21.3 defined by overlapping homozygous deletions in lung and breast tumour lines. Although mutation analysis of candidate TSGs in lung and breast cancers revealed only rare mutations, expression of one of the genes (RASSF1A) was absent in the majority of lung tumour cell lines analysed. Subsequently methylation of a CpG island in the promoter region of RASSF1A was demonstrated in a majority of small cell lung carcinomas and to a lesser extent in non-small cell lung carcinomas. To investigate the role of 3p TSGs in neural crest tumours, we (a) analysed phaeochromocytomas for 3p allele loss (n=41) and RASSF1A methylation (n=23) and (b) investigated 67 neuroblastomas for RASSF1A inactivation. 46% of phaeochromocytomas showed 3p allele loss (38.5% at 3p21.3). RASSF1A promoter region hypermethylation was found in 22% (5/23) of sporadic phaeochromocytomas and in 55% (37/67) of neuroblastomas analysed but RASSF1A mutations were not identified. In two neuroblastoma cell lines, methylation of RASSF1A correlated with loss of RASSF1A expression and RASSF1A expression was restored after treatment with the demethylating agent 5-azacytidine. As frequent methylation of the CASP8 gene has also been reported in neuroblastoma, we investigated whether RASSF1A and CASP8 methylation were independent or related events. CASP8 methylation was detected in 56% of neuroblastomas with RASSF1A methylation and 17% without RASSF1A methylation (P=0.0031). These results indicate that (a) RASSF1A inactivation by hypermethylation is a frequent event in neural crest tumorigenesis, particularly neuroblastoma, and that RASSF1A is a candidate 3p21.3 neuroblastoma TSG and (b) a subset of neuroblastomas may be characterized by a CpG island methylator phenotype.
 ...
PMID:RASSF1A promoter region CpG island hypermethylation in phaeochromocytomas and neuroblastoma tumours. 1170 29

Many oncogenes and tumour suppressor genes are connected with the steps of carcinogenesis. Fifteen patients with endometrial cancer were immunohistochemically examined for the presence of abnormal p53 protein. The immunopositivity was comparted in the cancer tissues and analyzed with the conventional clinicopathological prognostic factors as grade, stage, depth of myometrial invasion, lymph-vascular space invasion, metastases in the lymph nodes and metastases in the abdominal cavity. Abnormal expression of p53 was observed in 7 women with endometrial cancer and in 5 patients we observed moderate cytoplasmatic reaction for BCL-2. The correlation between the positive reaction reaction for p53 and BCL-2 means more aggressive tumor, respectively is a bad prognostic factor. The overexpression of p53 is a very important parameter for the progression of the endometrial cancer.
 ...
PMID:[Expression of p53 protein in women with endometrial cancer]. 1180 62

The tumour suppressor gene p53 is frequently mutated in human cancer. Tumour derived p53 mutants are usually transcriptionally inactive, but some mutants retain the ability to transactivate a subset of p53 target genes. In addition to simple loss of function, some p53 mutants may be carcinogenic through a dominant negative mechanism. Aiming at a more general classification of p53 mutants into predictive functional categories it is important to determine (i) which p53 mutants are dominant, (ii) what features characterize dominant mutants and (iii) whether dominance is target gene specific. The ability of 71 p53 mutants to inhibit wild type p53 was determined using a simple yeast transcriptional assay. Approximately 30% of the mutants were dominant. They preferentially affect highly conserved amino acids (P<0.005), which are frequently mutated in tumours (P<0.005), and usually located near the DNA binding surface of the protein (P<0.001). Different tumour-derived amino acid substitutions at the same codon usually have the same dominance phenotype. To determine whether the ability of p53 mutants to inhibit wild type p53 is target gene specific, the dominance towards p21, bax, and PIG3 binding sites was examined. Approximately 40% of the 45 mutants examined were dominant for the p21 (17/45) or PIG3 (20/45) responsive elements and 71% (32/45) were dominant for the bax responsive element. These differences are statistically significant (p21 vs bax, P<0.003; bax vs PIG3, P<0.02, Fisher's exact test) and defined a hierarchy of dominance. Finally, we extended the analysis to a group of mutants isolated in BRCA-associated tumours, some of which retained wild type level of transcription in yeast as well as in human cells, but show gain of function in transformation assays. Since transformation assays require transdominant inhibition of the endogenous wild type allele, one possible explanation for the behaviour of the BRCA-associated mutants is that they adopt conformations able to bind DNA alone but not in mixed tetramers with wild type p53. The yeast data do not support this explanation, because all BRCA-associated mutants that behaved as wild type in transcription assay were recessive in dominance assays.
 ...
PMID:Tumour p53 mutations exhibit promoter selective dominance over wild type p53. 1189 95

The gastric hormone gastrin regulates the organization of the gastric epithelium, but the cellular control mechanisms are yet unknown. Epithelial remodelling typically involves extracellular proteolysis mediated by the matrix metalloproteinases (MMPs). Since a gene-array analysis of the gastric cancer cell line AGS-G(R) suggested that gastrin increased MMP-9 expression, we examined the control of MMP-9 expression by gastrin. Gelatin zymography confirmed gastrin induction of MMP-9 in AGS-G(R) cells, but showed a small inhibition of MMP-2. Immunocytochemical studies showed that MMP-9 was localized to vesicles that appeared to traffic along the processes that were extended in response to gastrin. Gastrin stimulated the invasion of AGS-G(R) cells through artificial basement membrane, which was reduced by an inhibitor of MMP-2/-9. There was also an increase in MMP-9 in the stomach of patients with elevated plasma gastrin and multiple-endocrine neoplasia type 1 (MEN-1) syndrome, suggesting in vivo regulation of MMP-9 expression by gastrin. Finally, we showed that the expression of 1.9 kb of human MMP-9 gene promoter coupled with luciferase (MMP-9-luc) was increased 7.65+/-1.2-fold by gastrin, via a pathway which includes stimulation of protein kinase C, and activation of Raf and the mitogen-activated protein (MAP) kinase pathway. The tumour suppressor menin (which is mutated in MEN-1 syndrome) inhibited the expression of MMP-9-luc by gastrin. These results suggest that gastrin increases MMP-9 expression, which is associated with increased invasion, and this is a putative mechanism regulating remodelling of the gastric epithelium.
 ...
PMID:Gastrin-stimulated gastric epithelial cell invasion: the role and mechanism of increased matrix metalloproteinase 9 expression. 1197 60

Mutations in the adenomatous polyposis coli (APC) gene are not only responsible for familial adenomatous polyposis (FAP), but also play a rate-limiting role in the majority of sporadic colorectal cancers. Colorectal tumours are known to arise through a gradual series of histological changes, the so-called 'adenoma-carcinoma' sequence, each accompanied by a genetic alteration in a specific oncogene or tumour suppressor gene. Loss of APC function triggers this chain of molecular and histological changes. In general, an intestinal cell needs to comply with two essential requirements to develop into a cancer: it must acquire selective advantage to allow for the initial clonal expansion, and genetic instability to allow for multiple hits at other genes responsible for tumour progression and malignant transformation. Inactivation of APC seems to fulfill both requirements. In this short review, I will discuss the role played by APC in providing, when mutated, selective advantage, through constitutional activation of the Wnt signal transduction pathway, and chromosomal instability to the nascent intestinal tumor cell.
 ...
PMID:The APC gene in colorectal cancer. 1197 10

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.
 ...
PMID:The aggressive nature of the odontogenic keratocyst: is it a benign cystic neoplasm? Part 2. Proliferation and genetic studies. 1207 94


<< Previous 1 2 3 4 5 6 7 8 9 10