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)

Oncogene-induced senescence acts as a barrier against tumour formation and has been implicated as the mechanism preventing the transformation of benign melanocytic lesions that frequently harbour oncogenic B-RAF or N-RAS mutations. In the present study we systematically assessed the relative importance of the tumour suppressor proteins p53, p21(Waf1), pRb and p16(INK4a) in mediating oncogene-induced senescence in human melanocytes. We now show that oncogenic N-RAS induced senescence in melanocytes is associated with DNA damage, a potent DNA damage response and the activation of both the p16(INK4a)/pRb and p53/p21(Waf1) tumour suppressor pathways. Surprisingly neither the pharmacological inhibition of the DNA damage response pathway nor silencing of p53 expression had any detectable impact on oncogene-induced senescence in human melanocytes. Our data indicate that the pRb pathway is the dominant effector of senescence in these cells, as its specific inactivation delays the onset of senescence and weakens oncogene-induced proliferative arrest. Furthermore, we show that although both p16(INK4a) and p21(Waf1) are upregulated in response to N-RAS(Q61K), the activities of these CDK inhibitors are clearly distinct and only the loss of p16(INK4a) weakens senescence. We propose that the ability of p16(INK4a) to inhibit the cyclin D-dependent kinases and DNA replication, functions not shared by p21(Waf1), contribute to its role in senescence. Thus, in melanocytes with oncogenic signalling only p16(INK4a) can fully engage the pRb pathway to alter chromatin structure and silence the genes that are required for proliferation.
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PMID:The relative contributions of the p53 and pRb pathways in oncogene-induced melanocyte senescence. 2015 37

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.
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PMID:Clinical and molecular genetics of parathyroid neoplasms. 2083 39

Squamous cell carcinoma of the head and neck (SCCHN) arises as a consequence of multiple molecular events induced by the effects of various habits such as tobacco and use of alcoholic beverages, influenced by environmental factors, possibly viruses in some instances, against a background of heritable resistance or susceptibility. Oral squamous cell cancers have a similar aetiology. Genetic damage affects many chromosomes and genes, including oncogenes and tumour suppressor genes, and it is the accumulation of such genetic damage, possibly along with an impaired ability to repair this damage - an inherited trait in some cases - that appears to lead to carcinoma in some instances, sometimes via a clinically evident pre-malignant, or potentially malignant, lesion. This communication reviews the advances in the understanding of this complex and rapidly developing area of research over the past decade. Cytogenetic and molecular analyses have shown changes in several chromosomes in oral cancer, particularly in chromosomes 3, 9, 11, 13 and 17. Analyses of allelic losses has allowed for the identification of chromosomal regions harbouring tumour suppressor genes (TSGs). Impaired function of such genes or their products, or activation of oncogenes, or both, may be involved in carcinogenesis. Probably the most significant findings thus far have been in relation to TSGs with the discovery of p53 mutations on chromosome 17 as in many other tumours, indicating disturbed function of this TSG and some on chromosomes 3 and 9 (MTS-1) which may be of comparable or greater significance. Over-expression of oncogenes, especially those on chromosome 11 (PRAD-1, Int-2, hst-l, and bcl-1 in particular) has also been implicated in carcino-genesis. The analysis of microsatellite instability (MI or RER, replication error repair) in tumour specimens, which are associated with defects in DNA repair genes has provided a further method of assessing genetic damage in the genome of sporadic cancers. Microsatellite instability (MI) has been demonstrated in several carcinomas as well as SCCHN. These research findings have now reached the stage where it is becoming possible to begin to introduce them into clinical practice for the more sensitive detection of potentially malignant lesions, better diagnosis and prognostication, and hopefully, to start to develop novel therapies such as gene therapy.
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PMID:Genetic aberrations in squamous cell carcinoma of the head and neck (SCCHN), with reference to oral carcinoma (review). 2153 38


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