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)

The current state of knowledge of melanoma genetics is reviewed. Mutations in the tumour suppressor gene CDKN2A and in the oncogenes N-ras and H-ras seem to play the most important roles in the development and progression of malignant melanoma. Experimental studies to determine the role of ultraviolet (UV) light in the induction of melanoma have been hampered by a lack of suitable animal models. The commonly used laboratory animals are not susceptible to the induction of melanoma upon exposure to UV radiation (UVR) alone. Recent observations with four different animals have suggested, however, that UVR may be involved in the induction of melanoma. The most recent model consists of human skin grafted onto immunodeficient mice. To date, using this model, only the combination of UVB (280-320 nm) exposure and topical promoter treatment has led to the development of malignant melanoma. The wavelength dependency of the induction of melanoma has been established in the fish model Xiphophorus. The application of such an action spectrum to humans looks possible.
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PMID:Photobiology and genetics of malignant melanoma. 1196 26

Germline mutations in LKB1 (also known as STK11) are associated with Peutz-Jeghers syndrome (PJS), a disorder with predisposition to gastrointestinal polyposis and cancer. PJS polyps are unusual neoplasms characterized by marked epithelial and stromal overgrowth but have limited malignant potential. Here we show that Lkb1(+/-) mice develop intestinal polyps identical to those seen in individuals affected with PJS. Consistent with this in vivo tumour suppressor function, Lkb1 deficiency prevents culture-induced senescence without loss of Ink4a/Arf or p53. Despite compromised mortality, Lkb1(-/-) mouse embryonic fibroblasts show resistance to transformation by activated Ha-Ras either alone or with immortalizing oncogenes. This phenotype is in agreement with the paucity of mutations in Ras seen in PJS polyps and suggests that loss of Lkb1 function as an early neoplastic event renders cells resistant to subsequent oncogene-induced transformation. In addition, the Lkb1 transcriptome shows modulation of factors linked to angiogenesis, extracellular matrix remodelling, cell adhesion and inhibition of Ras transformation. Together, our data rationalize several features of PJS polyposis--notably its peculiar histopathological presentation and limited malignant potential--and place Lkb1 in a distinct class of tumour suppressors.
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PMID:Loss of the Lkb1 tumour suppressor provokes intestinal polyposis but resistance to transformation. 1222 50

For understanding of the pathophysiology of multiple myeloma, features of the malignant clone and changes induced by the bone-marrow microenvironment are equally important. Multiple myeloma plasma cells, which originate from postfollicular B cells, are characterised by complex chromosomal aberrations. Among the earliest genetic events are translocations of the immunoglobulin heavy-chain gene locus, which leads to dysregulation of oncogenes at translocation partner regions (cyclin D1 at 11q13, FGFR3/MMSET at 4p16.3, c-MAF at 16q23, and cyclin D3 at 6p21), and deletions of 13q14, the site of a putative tumour suppressor gene, which is an adverse prognostic indicator. Additional molecular events include epigenetic changes and activation of oncogenes (mutations of N-RAS and K-RAS, and changes in c-MYC), which are usually associated with disease progression. Bone-marrow stromal cells support growth and survival of multiple myeloma cells via various cytokines. Osteoclast activity factors (in particular MIP1alpha) and imbalances between RANKL and osteoprotegerin are major factors for the development of myeloma bone disease. Further characterisation of crucial events in the development of monoclonal gammopathies by novel techniques such as global gene expression profiling will contribute to a molecular classification of multiple myeloma and foster future therapeutic approaches.
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PMID:New insights into the pathophysiology of multiple myeloma. 1296 77

Oral squamous cell carcinoma (OSCC) is a common cancer characterised by low survival rate and poor prognosis. The multistep process of oral carcinogenesis is affected by multiple genetic events such as alterations of oncogenes and tumour suppressor genes. The use of appropriate experimental animal models that accurately represent the cellular and molecular changes which are associated with the initiation and progression of human oral cancer is of crucial importance. The Syrian golden hamster cheek pouch oral carcinogenesis model is the best known animal system that closely correlates events involved in the development of premalignant and malignant human oral cancers. Therefore, we established an experimental system of chemically induced oral carcinogenesis in hamsters, in order to study different stages of tumour formation: normal mucosa, hyperkeratosis, hyperplasia, dysplasia, early invasion, well differentiated OSCC and moderately differentiated OSCC. We investigated the expression of oncogenes EGFR, erbB2, erbB3, FGFR-2, FGFR-3, c-myc, N-ras, ets-1, H-ras, c-fos and c-jun, apoptosis markers Bax and Bcl-2, tumour suppressor genes p53 and p16, and cell proliferation marker Ki-67 in the sequential stages of hamster oral oncogenesis. Here, we describe the findings of the experimental model in regard to the involvement of signal transduction pathways in every stage of cancer development. Increased apoptosis and cell proliferation were observed in early stages of oral oncogenesis. Furthermore, the increased expression of transmembrane receptors (EGFR, erbB2, FGFR-2 and FGFR-3) as well as the increased expression of nuclear transcriptional factors in early stages of oral cancer indicates that these molecules may be used as early prognostic factors for the progression of OSCC. Since the expression of both H-ras and N-ras do not seem to affect signal transduction during oral oncogenesis, it can be assumed that a different signalling pathway, such as the PI3K and/or PLCgamma pathway, may be implicated in the pathogenesis of OSCC.
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PMID:The hamster model of sequential oral oncogenesis. 1806 31

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

miR-663 is a tumour suppressor that is potentially regulated by modification of CpG islands. Whether aberrant methylation is one of the reasons for miR-663 down-regulation in some malignant cells and whether miR-663 targets oncogenes warrants further research. In the present study, we report that the CpG islands in the upstream region of pre-miR-663 are aberrantly methylated in the k-562 cell line and in the white blood cells of some chronic myelogenous leukaemia patients, and also that H-ras is one of the genes targeted by miR-663. Over-expression of miR-663 may suppress proliferation of the k-562 cell line in part by enhancing cell apoptosis.
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PMID:The epigenetically-regulated miR-663 targets H-ras in K-562 cells. 2395 23

The regulatory transcriptional factor PATZ1 is constantly downregulated in human thyroid cancer where it acts as a tumour suppressor by targeting p53-dependent genes involved in Epithelial-Mesenchymal Transition and cell migration. The aim of the present work was to elucidate the upstream signalling mechanisms regulating PATZ1 expression in thyroid cancer cells. The bioinformatics search for microRNAs able to potentially target PATZ1 led to the identification of several miRNAs. Among them we focused on the miR-29b since it was found upregulated in rat thyroid differentiated cells transformed by the Ha-Ras oncogene towards a high proliferating and high migratory phenotype resembling that of anaplastic carcinomas. Functional assays confirmed PATZ1 as a target of miR-29b, and, consistently, an inverse correlation between miR-29b and PATZ1 protein levels was found upon induction of Ha-Ras oncogene expression in these cells. Interestingly, restoration of PATZ1 expression in rat thyroid cells stably expressing the Ha-Ras oncogene decreased cell proliferation and migration, indicating a key role of PATZ1 in Ras-driven thyroid transformation. Together, these results suggest a novel mechanism regulating PATZ1 expression based on the upregulation of miR-29b expression induced by Ras oncogene.
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PMID:PATZ1 is a target of miR-29b that is induced by Ha-Ras oncogene in rat thyroid cells. 2712 50


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