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)

Typical carcinoid, atypical carcinoid, and small cell lung cancer (SCLC) fall within the spectrum of neuroendocrine lung neoplasms. This paper investigates the immunohistochemical expression of the products of tumour suppressor genes p53 and retinoblastoma (RB), together with proliferation (PCNA and Ki67) and neuroendocrine differentiation markers, in 14 typical carcinoids, ten atypical carcinoids, four borderline atypical carcinoid/SCLC, and 11 SCLC. We demonstrated that the phosphoprotein p53 and RB product can be immunolocalized on routine histological material. p53 protein was absent in all typical and atypical carcinoids, while it was abnormally expressed in eight SCLC and one borderline case. RB product was detected in all typical carcinoids and in two atypical carcinoids, while it was consistently absent in the other cases. PCNA-labelled cells were less than 4 per cent in typical carcinoids, about 40 per cent in atypical carcinoids, and over 70 per cent in SCLC. PCNA labelling index discriminates between typical and atypical carcinoids. Neuroendocrine differentiation was evaluated by a semi-quantitative method: a mean score value was obtained, which was high in typical carcinoids, intermediate in atypical carcinoids, and low in SCLC. Our data was obtained, which was high in typical carcinoids, intermediate in atypical carcinoids, and low in SCLC. Our data show that the decrease in neuroendocrine features from typical carcinoid to SCLC is paralleled by an increase in proliferative activity and by an altered expression of tumour suppressor gene products. The above findings have diagnostic relevance.
 ...
PMID:Tumour suppressor gene products, proliferation, and differentiation markers in lung neuroendocrine neoplasms. 135 31

The tumorigenesis of neuroendocrine tumours remains poorly understood, although a minority, the familial multiple endocrine neoplasia (MEN 1 and MEN 2), are known to be of uncommon genetic origin. Mutation of the tumour suppressor gene, p53, is now known to be a common genetic alteration in about half of all types of non-endocrine cancers. In the present study, immunocytochemistry using the monoclonal anti-p53 antibody, DO-7, has been employed to investigate the accumulation of p53 immunoreactivity in a wide range of primary neuroendocrine tumours. Tumours (n = 109) were fixed and processed to paraffin wax according to a constant protocol. Sections were subjected to microwave antigen retrieval prior to immunostaining for p53. Positive nuclear immunostaining was observed in one medullary carcinoma of the thyroid (MCT), one lung carcinoid, and five small cell carcinomas of the lung (SCCL). All other tumour samples were consistently negative. As the neoplasia investigated in this study comprised a wide spectrum of neuroendocrine tumour types and ranged from minute, relatively benign lesions to malignant metastasizing disease and as there was no relationship between the presence of p53 overexpression and clinico-pathological features, the present study suggests that p53 gene mutation may be relatively unimportant in the genesis of neuroendocrine tumours.
 ...
PMID:Overexpression of the tumour suppressor gene p53 is not implicated in neuroendocrine tumour carcinogenesis. 877 44

Carcinoid tumours may develop from enterochromaffin cells in the gastrointestinal tract. Benign insulin-producing tumours may develop from islet cells, whereas other islet cell tumours might derive from multipotent stem cells in the pancreatic ducts. The idea that multiple endocrine neoplasia type 1 (MEN-1) tumours in the pancreas originate from multipotent stem cells is supported by our demonstration that CD44 is expressed in exocrine cells, in gastrin-producing endocrine cells only and in some non-functioning islet cell tumours; there are no gastrin-producing cells in the adult pancreas. We have identified phospholipase C beta 3 (PLC beta 3) as the gene implicated in MEN-1. It appears to be a tumour suppressor gene since it is expressed in endocrine pancreatic tumours, some lung carcinoids, and medullary thyroid carcinomas. So neuroendocrine tumours might have a dual growth-regulating system, involving both traditional growth factors through the tyrosine kinase system and also G-protein-mediated growth signals. Deletion of PLC beta 3, which is an important enzyme in the signal transduction pathway of G-protein-mediated signals, might be important in the growth regulation of neuroendocrine tumours. It is proposed that its deletion causes dysregulation of growth control in neuroendocrine cells, with possible distortion of the apoptotic process. In the last stage of the disease, tumour biology is altered and becomes more aggressive. Further, chromogranin A may be both a tumour marker for neuroendocrine tumours and a growth-promoting agent for neuroendocrine tumour cells; it is a very good marker of tumour mass but is also related to poor prognosis of survival. Mutation analyses of PLC beta 3 and studies of the growth-promoting effect of chromogranin are ongoing and should lead to more effective therapies.
 ...
PMID:Biological aspects of neuroendocrine gastro-enteropancreatic tumours. 881 67

The development of some endocrine tumours, such as medullary thyroid carcinomas, phaeochromocytomas, anterior pituitary adenomas, and parathyroid adenomas involve a putative tumour suppressor gene located on chromosome 1p32-pter, a region that represents 111 cM. In order to refine the location of this gene, 93 endocrine tumours (39 parathyroid adenomas, 40 anterior pituitary adenomas, seven pancreatic islet cell adenomas, and seven carcinoids) were investigated for loss of tumour heterozygosity (LOH) using the seven polymorphic loci 1pter-D1S228-D1S507-D1S234-D1S476-D1S22 0-D1S207-D1S206-1cen. LOH was detected in 27% of the parathyroid tumours and in 7.5% of the pituitary tumours, but in none of the pancreatic islet cell or carcinoid tumours. In addition, seven of the 10 parathyroid tumours that showed LOH of chromosome 1p facilitated a more precise mapping of this putative tumour suppressor gene; five tumours involved a loss only of the telomeric locus D1S228, whereas two other tumours showed LOH at the centromeric loci D1S507, D1S234, D1S476, and D1S220, but not D1S228. Thus, our results have mapped this tumour suppressor gene implicated in endocrine tumours to a 4 cM region flanked by D1S228 and D1S507 on chromosome 1p35-p36.
 ...
PMID:Localisation of a gene causing endocrine neoplasia to a 4 cM region on chromosome 1p35-p36. 927 50

The molecular mechanisms leading to Cushing's disease are unclear. Inhibitors of cyclin-cyclin dependent kinase (CDK) complexes are regulators of the cell cycle and may function as tumour suppressor genes, many of which have been involved in the pathogenesis of several human malignancies. A member of this family, the p27/kip1 gene, maps to chromosome 12p13 and encodes an inhibitor of several cyclin-CDK complexes; these control the progression of the cell cycle from G1 to S-phase. Complete lack of p27/kip1 function, as occurs in the p27/kip1 'knockout' mouse, produces a complex phenotype associated with the development of pituitary tumours, specifically those of the intermediate lobe corticotrophs. We therefore investigated whether structural and functional abnormalities of the p27/kip1 gene and loss at the chromosome 12p13 region were present in human corticotrophin (ACTH)-secreting pituitary tumours. We studied 21 pituitary tumours, of which 20 were ACTH-secreting (two of these had biochemical and histological features of 'intermediate-lobe' tumours and one was malignant) while the remaining tumour was a prolactinoma; three ectopic secretors of ACTH (two bronchial and one thymic carcinoid); and a non-secretory thymic carcinoid. The whole coding region of the p27/ kip1 gene was screened for mutations by PCR-SSCP analysis and/or direct sequencing, while tumour mRNA expression was analysed by means of a semi-quantitative duplex PCR. Three polymorphic microsatellite markers of the 12p13 region were used to assess loss of heterozygosity (LOH) in 12 samples. Finally, tumour p27/kip1 protein expression was assessed by immunohistochemistry using a monoclonal antibody in 12 samples suitable for analysis. No sequence abnormalities were found in any of the samples other than a previously-described polymorphism. No LOH was observed in the tumours analysed. p27/kip1 mRNA expression was similar in tumour samples in comparison with normal pituitaries. Seven of the eight corticotroph tumours analysed by immunohistochemistry stained positive for p27/kip1, including the intermediate lobe. The only malignant pituitary tumour in the original series showed an absence of staining for p27/kip1. In addition, the three carcinoid tumours studied were negative on immunohistochemistry. Of a further three malignant pituitary tumours assessed, two (including a prolactinoma) were essentially negative, while the third was moderately positive. We conclude that mutations of the p27/kip1 gene, deletions of the 12p13 area or changes in expression, are not a general feature of corticotroph tumours, even those with intermediate lobe characteristics. However, other mechanisms of p27/kip1 inactivation, such as an abnormality at the post-translational level, may be related to more aggressive histological subtypes of ACTH-secreting and possibly other pituitary tumours.
 ...
PMID:Mutation and expression analysis of the p27/kip1 gene in corticotrophin-secreting tumours. 946 44

Several genetic aberrations have been implicated in the carcinogenesis of small cell lung carcinomas (SCLCs), including tumour suppressor gene p53 deletion and mutation and amplification of the myc family proto-oncogenes. However, their exact ontogeny and carcinogenesis remain unknown. There are no proven aetiological factors for lung carcinoid tumours. Recent evidence suggests that the genetic regulation of apoptosis is of critical importance during tumourigenesis and that oncogene and tumour suppressor genes can regulate the rate, or susceptibility, of cells to undergo apoptosis. In this study, the expression of Bcl-2 protein has been investigated in 77 primary lung neuroendocrine tumours, including 55 SCLCs and 22 carcinoid tumours, and compared with p53 expression. Of the 77 tumours studied, Bcl-2 immunoreactivity was present in 80 per cent of SCLCs, 43 per cent of typical, and 67 per cent of atypical carcinoid tumours with more than 10 per cent tumour cell positivity. Western and Northern blot analysis revealed that carcinoid tumours expressed the 26 kD protein and bcl-2 transcripts. Whereas 42 per cent of the SCLCs studied displayed p53 protein immunoreactivity in more than 10 per cent of tumour cells, p53 positivity was not found in lung carcinoid tumours. There are statistical differences in Bcl-2 and p53 expression between SCLCs and lung carcinoid tumours. These results suggest that disregulation of the genetic mechanisms controlling apoptosis is a critical step in the progression of SCLC, and the expression of Bcl-2 is involved in the pathogenesis of SCLC and lung carcinoid tumours. The genetic complementation of simultaneously deregulated Bcl-2 and p53 may be implicated in the multistep tumourigenesis of small cell lung cancer.
 ...
PMID:Expression of Bcl-2 in lung neuroendocrine tumours: comparison with p53. 961 75

The pathogenesis and interrelationships of neuroendocrine lung carcinomas are not well understood. Tissue macro-arrays prepared from surgical resection specimens from 35 patients with typical carcinoid (TC), six with atypical carcinoid (AC), 13 with large cell neuroendocrine carcinoma (LCNEC), and 15 with small cell lung carcinoma (SCLC) were investigated by fluorescence in situ hybridization (FISH) and immunohistochemistry. Hybridizations with locus-specific DNA probes demonstrated a high incidence of deletion for the tumour suppressor genes p53 and retinoblastoma (Rb), and for the oncogene cyclin D1, comparable in all carcinoma types. Similarly, an increase of DNA copy number for the Her-2/neu and c-myc oncogenes was noted in all neoplasms. A more detailed quantitative analysis of the results, however, demonstrated increasing numbers of cells harbouring these genomic alterations, from low-grade TC to highly malignant SCLC, with the exception of cyclin D1 deletion. Mutations of the p53 and Rb genes, as assayed by immunohistochemical studies, were observed at high incidence in high-grade carcinomas, compared with a low incidence in the low-grade carcinomas. Conversely, in all carcinoma types, neither membrane-bound Her-2/neu nor nuclear cyclin D1 was detected. It is concluded that structural genomic alterations are frequent in neuroendocrine lung carcinomas and that their occurrence may be underestimated by immunohistochemical studies alone. The quantitative expansion of the Rb, p53, c-myc, and Her-2/neu alterations towards high-grade carcinomas suggests common pathogenetic mechanisms in the spectrum of these neoplasms.
 ...
PMID:Quantitative expansion of structural genomic alterations in the spectrum of neuroendocrine lung carcinomas. 1192 Jul 36

Somatostatin is an inhibitory neuropeptide, which acts on various targets throughout the body to regulate a variety of physiological functions including inhibition of endocrine and exocrine secretions, modulation of neurotransmission, motor and cognitive functions, inhibition of intestinal motility, absorption of nutrients and ions, vascular contractility and inhibition of normal and tumour cell proliferation. It exerts its effects through interaction with five somatostatin receptors (sst1-sst5), which belong to the family of G-protein-coupled receptors with seven transmembrane spanning domains and are variably expressed in a variety of tumours such as gastroenteropancreatic tumours, pituitary tumours, and carcinoid tumours. This review covers the present knowledge regarding the molecular mechanisms involved in somatostatin antineoplastic activity. Evidence that sst2 receptor acts as a tumour suppressor is also discussed.
 ...
PMID:Somatostatin receptors and regulation of cell proliferation. 1507 5

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominantly inherited disorder, characterised by the occurrence of tumours of the parathyroid glands, the pancreatic islets, the pituitary gland, the adrenal glands and neuroendocrine carcinoid tumours. Carcinoid tumours of the thymus and pancreatic-duodenal gastrinomas are the most harmful tumour types, since these tumours have malignant potential and curative treatment is difficult to achieve.MEN1 is caused by germline mutations of the MEN1 tumour suppressor gene. Mutation analysis enables mutation carriers to be identified. MEN1 patients and their family members, family members of mutation carriers and patients who are clinically suspected to be carriers of a MEN1 gene mutation are eligible for mutation analysis. MEN1-associated tumours can be detected and treated at an early stage through periodical clinical monitoring of mutation carriers.
 ...
PMID:Diagnosis and Management of Multiple Endocrine Neoplasia Type 1 (MEN1). 2022 25

Somatic gene mutations constitute key events in the malignant transformation of human cells. Somatic mutation can either actively speed up the growth of tumour cells or relax the growth constraints normally imposed upon them, thereby conferring a selective (proliferative) advantage at the cellular level. Neurofibromatosis type-1 (NF1) affects 1/3,000-4,000 individuals worldwide and is caused by the inactivation of the NF1 tumour suppressor gene, which encodes the protein neurofibromin. Consistent with Knudson's two-hit hypothesis, NF1 patients harbouring a heterozygous germline NF1 mutation develop neurofibromas upon somatic mutation of the second, wild-type, NF1 allele. While the identification of somatic mutations in NF1 patients has always been problematic on account of the extensive cellular heterogeneity manifested by neurofibromas, the classification of NF1 somatic mutations is a prerequisite for understanding the complex molecular mechanisms underlying NF1 tumorigenesis. Here, the known somatic mutational spectrum for the NF1 gene in a range of NF1-associated neoplasms - including peripheral nerve sheath tumours (neurofibromas), malignant peripheral nerve sheath tumours, gastrointestinal stromal tumours, gastric carcinoid, juvenile myelomonocytic leukaemia, glomus tumours, astrocytomas and phaeochromocytomas - have been collated and analysed.
 ...
PMID:Neurofibromatosis type 1-associated tumours: their somatic mutational spectrum and pathogenesis. 2215 6


1 2 Next >>