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)

Treatment options for pancreatic cancer have limited success and it is therefore an appropriate target for the development of new strategies, including gene therapy. Gene therapy approaches include inhibition of activated oncogenes (KRAS, LSM1) with antisense and RNA interference strategies, replacement of inactivated tumour suppressor genes (TP53, CDKN2A, CDKN1A), targeting of cell signalling pathways, gene-directed prodrug-activation therapies and the use of replication-competent oncolytic viruses. Angiogenesis and apoptosis have also been targeted for gene therapy. Clinical trials of gene therapy have shown only moderate anti-tumour effects. As there are many genetic abnormalities in pancreatic cancer, strategies combining different targets or indeed different modalities of treatment, may be more successful. Identification of new targets and improvements in delivery and targeting may further improve the efficacy of gene therapy in pancreatic cancer.
Best Pract Res Clin Gastroenterol 2006 Apr
PMID:Gene therapy developments for pancreatic cancer. 1654 28

Hereditary multiple exostoses (HME) is an autosomal-dominant disorder characterized by the development of benign tumours, multiple osteochondromas (exostoses), growing outward from the metaphyses of long bones. Birth prevalence is estimated to be one in 50,000, and the severity of the disease is variable. Osteochondromas may cause complications including pain, deformities and shortening of the long bones, restricted motion of joints, nerve or blood vessel compression, and malignant transformation (5% of cases) in adulthood. HME is a genetically heterogeneous disorder and is associated with mutations in EXT1 or EXT2 genes, which are both tumour suppressor genes. EXT genes encode glycosyltransferases, termed 'exostosins', which are involved in the biosynthesis of heparan sulphate. Enchondromatosis (or Ollier disease) is characterized by the presence of intra-osseous benign cartilaginous tumours. The estimated prevalence of the disease is one in 100,000. An asymmetrical distribution of cartilage lesions is observed in the disease. The number, size and location of the enchondromas can be extremely variable between patients. Clinical problems caused by enchondromas include skeletal deformities, limb length discrepancy, pain and the potential risk for malignant change to chondrosarcoma (20-50% of cases). The condition in which multiple enchondromas is associated with haemangiomas is known as 'Maffucci syndrome'. Ollier disease and Maffucci syndrome are not usually inherited disorders.
Best Pract Res Clin Rheumatol 2008 Mar
PMID:Hereditary multiple exostoses and enchondromatosis. 1832 80

Uterine fibroids are the most common benign tumour of the female genital tract. However, their true prevalence is probably under-estimated, as the incidence at histology is more than double the clinical incidence. Recent longitudinal studies have estimated that the lifetime risk of fibroids in a woman over the age of 45 years is more than 60%, with incidence higher in blacks than in whites. The cause of fibroids remains unclear and their biology poorly understood. No single candidate gene has been detected for commonly occurring uterine fibroids. However, the occurrence of rare uterine fibroid syndromes, such as multiple cutaneous and uterine leiomyomatosis, has been traced to the gene that codes for the mitochondrial enzyme, fumarate hydratase. Cytogenetic abnormalities, particularly deletions of chromosome 7, which are found in up to 50% of fibroid specimens, seem to be secondary rather than primary events, and investigations into the role of tumour suppressor genes have yielded conflicting results. The key regulators of fibroid growth are ovarian steroids, both oestrogen and progestogen, growth factors and angiogenesis, and the process of apoptosis. Black race, heredity, nulliparity, obesity, polycystic ovary syndrome, diabetes and hypertension are associated with increased risk of fibroids, and there is emerging evidence that familial predisposition to fibroids is associated with a distinct pattern of clinical and molecular features compared with fibroids in families without this prevalence.
Best Pract Res Clin Obstet Gynaecol 2008 Aug
PMID:Incidence, aetiology and epidemiology of uterine fibroids. 1853 13

The study of the clonality of adrenocortical tumours (ACTs) has shown that adrenocortical cancers (ACCs) are of monoclonal origin. Numerous chromosomal alterations have been observed in ACCs, and they are much more frequent than in adrenocortical adenomas. Progress in the genetics of familial syndromes associated with ACTs helped to identify significant somatic molecular alterations in sporadic adult ACCs. Somatic mutations of the tumour suppressor gene TP53 are observed in a third of ACCs. Interestingly, allelic losses (LOH) at the TP53 locus (17p13) are very frequent, observed in more than 85% of ACCs. The insulin-like growth factor II (IGF-II) locus (11p15) is imprinted. IGF-II is over-expressed in 90% of ACCs. Transcriptome studies have identified an IGF-II cluster of genes significantly over-expressed in ACCs. Transcriptome analysis suggests also that the Wnt/beta-catenin signalling pathway is activated in ACT. About a third of ACCs harbours somatic activating mutations of the beta-catenin gene. This recent progress in the molecular genetics of ACC has led to the development of new molecular markers for the diagnosis of malignancy; these might also help to identify prognostic markers of ACC and may ultimately lead to novel therapeutic approaches.
Best Pract Res Clin Endocrinol Metab 2009 Apr
PMID:Pathogenesis of adrenocortical cancer. 1950 Jul 68

The pathogenesis of tumour formation in the anterior pituitary has been intensively studied, but the causative mechanisms involved in pituitary cell transformation and tumourigenesis remain elusive. Most pituitary tumours are sporadic, but some arise as a component of genetic syndromes such as the McCune-Albright syndrome, multiple endocrine neoplasia type 1, Carney complex and, the most recently described, a MEN1-like phenotype (MEN4) and pituitary adenoma predisposition syndromes. Some specific genes have been identified that predispose to pituitary neoplasia (GNAS, MEN1, PRKAR1A, CDKN1B and AIP), but these are rarely involved in the pathogenesis of sporadic tumours. Mutations of tumour suppressor genes or oncogenes, as seen in more common cancers, do not seem to play an important role in the great majority of pituitary adenomas. The pituitary tumour transforming gene (PTTG; securin) was the first transforming gene found to be highly expressed in pituitary tumour cells, and seems to play an important role in the process of oncogenesis. Many tumour suppressor genes, especially those involved in the regulation of the cell cycle, are under-expressed, most often by epigenetic modulation - usually promoter hypermethylation - but the regulator of these co-ordinated series of methylations is also unclear. Cell signalling abnormalities have been identified in pituitary tumours, but their genetic basis is unknown. Both Raf/MEK/ERK and PI3K/Akt/mTOR pathways are over-expressed and/or over-activated in pituitary tumours: these pathways share a common root, including initial activation related to the tyrosine kinase receptor, and we speculate that a change to these receptors or their relationship to membrane matrix-related proteins may be an early event in pituitary tumourigenesis.
Best Pract Res Clin Endocrinol Metab 2009 Oct
PMID:The pathophysiology of pituitary adenomas. 1994 21

Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal-dominant disorder characterised by the occurrence of tumours of the parathyroids, pancreas and anterior pituitary. The MEN1 gene, consists of 10 exons that encode a 610-amino acid protein referred to as Menin. Menin is predominantly a nuclear protein that has roles in transcriptional regulation, genome stability, cell division and proliferation. Germ-line mutations usually result in MEN1 or occasionally in an allelic variant referred to as Familial Isolated Hyperparathyroidism (FIHP). MEN1 tumours frequently have loss of heterozygosity (LOH) of the MEN1 locus, which is consistent with a tumour suppressor role of MEN1. Furthermore, somatic abnormalities of MEN1 have been reported in MEN1 and non-MEN1 endocrine tumours. To date, over 1300 mutations have been reported, and the majority (>70%) of these are predicted to lead to truncated forms of Menin. The mutations are scattered throughout the >9 kb genomic sequence of the MEN1 gene. Four, which consist of c.249_252delGTCT (deletion at codons 83-84), c.1546_1547insC (insertion at codon 516), c.1378C>T (Arg460Ter) and c.628_631delACAG (deletion at codons 210-211) have been reported to occur frequently in 4.5%, 2.7%, 2.6% and 2.5% of families, respectively. However, a comparison of the clinical features in patients and their families with the same mutations reveals an absence of phenotype-genotype correlations. The majority of MEN1 mutations are likely to disrupt the interactions of Menin with other proteins and thereby alter critical events in cell cycle regulation and proliferation.
Best Pract Res Clin Endocrinol Metab 2010 Jun
PMID:Multiple endocrine neoplasia type 1 (MEN1). 2083 29

von Hippel-Lindau disease (VHL) disease increases susceptibility to several malignancies, including renal cell carcinoma, haemangioblastomas of the central nervous system or retina and phaeochromocytomas. The VHL tumour suppressor gene, responsible for the disease, encodes for a major regulator of the hypoxic response by targeting the transcription factor hypoxia inducible factor (HIF) for degradation. In this review, we present a synopsis of clinical features of the disease and emphasise unique aspects of VHL syndrome in the paediatric population. Genotype-phenotype associations based on the risk of phaeochromocytoma have pointed to the existence of additional, HIF-independent functions of VHL that remain underexplored. We also examine the progress on these pleiotropic roles of VHL, which contribute to explain clinical features of VHL disease. These advances have important translational implications and are likely to offer a new host of therapeutic options to individuals affected by the disease in the future.
Best Pract Res Clin Endocrinol Metab 2010 Jun
PMID:VHL disease. 2083 32

Neurofibromatosis type 1 (NF-1) and tuberous sclerosis complex (TSC) are two familial syndromes known as phakomatoses that may be associated with endocrine tumours. These hereditary cutaneous conditions affect the central nervous system and are characterised by the development of hamartomas. Over the past 20 years, there have been major advances in our understanding of the molecular basis of these diseases. Both NF-1 and TSC are disorders of unregulated progression through the cell cycle, in which causative genes behave as tumour suppressor genes. The pathogenesis of these familial syndromes is linked by the shared regulation of a common pathway, the protein kinase mammalian target of rapamycin (mTOR). Additional related disorders that also converge on the mTOR pathway include Peutz-Jeghers syndrome and Cowden syndrome. All of these inherited cancer syndromes are associated with characteristic skin findings that offer a clue to their recognition and treatment. The discovery of mTOR inhibitors has led to a possible new therapeutic modality for patients with endocrine tumours as part of these familial syndromes.
Best Pract Res Clin Endocrinol Metab 2010 Jun
PMID:Endocrine tumours in neurofibromatosis type 1, tuberous sclerosis and related syndromes. 2083 35

Primary hyperparathyroidism (HPT) results from the excessive secretion of parathyroid hormone from parathyroid tumours. While most HPT is sporadic, it is associated with a familial syndrome in a minority of cases. The study of these syndromes has helped define the pathophysiology of both familial and sporadic parathyroid neoplasms. Investigation of kindred with multiple endocrine neoplasia type 1 (MEN1) and the hyperparathyroidism-jaw tumour syndrome (HPT-JT) led to the discovery of the tumour suppressor genes MEN1 and HRPT2. We now recognise that somatic mutations in MEN1 and HRPT2 tumour suppressor genes are frequent events in sporadic parathyroid adenomas and carcinomas, respectively. Parathyroid tumours in the MEN2A syndrome result from mutational activation of the RET oncogene. The CCND1/PRAD1 oncogene was discovered by analysis of sporadic parathyroid tumours. Studies of familial isolated HPT and analysis of chromosomal loss and gain in parathyroid tumours suggest that other genes relevant to parathyroid neoplasia await identification.
Best Pract Res Clin Endocrinol Metab 2010 Jun
PMID:Clinical and molecular genetics of parathyroid neoplasms. 2083 39

Hepatocellular carcinoma is related to various etiologies including hepatitis B, hepatitis C, high alcohol intake, aflatoxin B1 and metabolic syndrome. Most of the time HCC developed on cirrhosis. Consequently, the mechanisms of carcinogenesis of these different risk factors are difficult to separate from the events leading to cirrhosis. In contrast, aflatoxin B1 and hepatitis B have a clear direct oncogenic role through point mutations in the TP53 tumour suppressor gene and insertional mutagenesis respectively. Finally, next-generation sequencing and transcriptome analysis will refine our knowledge of the relationship between aetiology and the genetic events that draw the mutational landscape of hepatocellular carcinoma.
Best Pract Res Clin Gastroenterol 2014 Oct
PMID:Pathogenesis of hepatocellular carcinoma according to aetiology. 2526 Mar 19


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