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

The development of multi-cellular organisms is regulated by the ordered definition of gene expression programmes that govern cell proliferation and differentiation. Although differential gene activity is mainly controlled by transcription factors, it is also dependent upon the underlying chromatin structure, which can stabilize transcriptional "on" or "off" states. We have recently isolated human (SUV39H1) and mouse (Suv39h1) histone methyltransferases (HMTases) and shown that they are important regulators for the organization of repressive chromatin domains. To investigate whether a SUV39H1-induced modulation of heterochromatin would affect mammalian development, we generated transgenic mice that over-express the SUV39H1 HMTase early during embryogenesis. SUV39H1 transgenic mice are growth retarded, display a weak penetrance of skeletal transformations and are largely characterized by impaired erythroid differentiation, consistent with highest transgene expression in foetal liver. Ex vivo transgenic foetal liver cultures initially contain reduced numbers of cells in G1 but progress to immortalized erythroblasts that are compromised in executing an erythroid differentiation programme. The outgrowing SUV39H1-immortalized erythroblasts can maintain a diploid karyotype despite deregulation of several tumour suppressor proteins and dispersed distribution of the heterochromatin component HP1. Together, these data provide evidence for a role of the SUV39H1 HMTase during the mammalian development and indicate a possible function for higher-order chromatin in contributing to the balance between proliferation and differentiation potentials of progenitor cells.
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PMID:Over-expression of the SUV39H1 histone methyltransferase induces altered proliferation and differentiation in transgenic mice. 1152 Jun 70

The pRb tumour suppressor protein has a central role in coordinating early cell cycle progression. An important level of control imposed on pRb occurs through post-translational modification, for example, phosphorylation. We describe here a new level of regulation on pRb, mediated through the targeted methylation of lysine residues, by the methyltransferase Set7/9. Set7/9 methylates the C-terminal region of pRb, both in vitro and in cells, and methylated pRb interacts with heterochromatin protein HP1. pRb methylation is required for pRb-dependent cell cycle arrest and transcriptional repression, as well as pRb-dependent differentiation. Our results indicate that methylation can influence the properties of pRb, and raise the interesting possibility that methylation modulates pRb tumour suppressor activity.
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PMID:Lysine methylation regulates the pRb tumour suppressor protein. 2014 18

An emerging vision for toxicity testing in the 21st century foresees in vitro assays assuming the leading role in testing for chemical hazards, including testing for carcinogenicity. Toxicity will be determined by monitoring key steps in functionally validated molecular pathways, using tests designed to reveal chemically-induced perturbations that lead to adverse phenotypic endpoints in cultured human cells. Risk assessments would subsequently be derived from the causal in vitro endpoints and concentration vs. effect data extrapolated to human in vivo concentrations. Much direct experimental evidence now shows that disruption of epigenetic processes by chemicals is a carcinogenic mode of action that leads to altered gene functions playing causal roles in cancer initiation and progression. In assessing chemical safety, it would therefore be advantageous to consider an emerging class of carcinogens, the epigenotoxicants, with the ability to change chromatin and/or DNA marks by direct or indirect effects on the activities of enzymes (writers, erasers/editors, remodelers and readers) that convey the epigenetic information. Evidence is reviewed supporting a strategy for in vitro hazard identification of carcinogens that induce toxicity through disturbance of functional epigenetic pathways in human somatic cells, leading to inactivated tumour suppressor genes and carcinogenesis. In the context of human cell transformation models, these in vitro pathway measurements ensure high biological relevance to the apical endpoint of cancer. Four causal mechanisms participating in pathways to persistent epigenetic gene silencing were considered: covalent histone modification, nucleosome remodeling, non-coding RNA interaction and DNA methylation. Within these four interacting mechanisms, 25 epigenetic toxicity pathway components (SET1, MLL1, KDM5, G9A, SUV39H1, SETDB1, EZH2, JMJD3, CBX7, CBX8, BMI, SUZ12, HP1, MPP8, DNMT1, DNMT3A, DNMT3B, TET1, MeCP2, SETDB2, BAZ2A, UHRF1, CTCF, HOTAIR and ANRIL) were found to have experimental evidence showing that functional perturbations played "driver" roles in human cellular transformation. Measurement of epigenotoxicants presents challenges for short-term carcinogenicity testing, especially in the high-throughput modes emphasized in the Tox21 chemicals testing approach. There is need to develop and validate in vitro tests to detect both, locus-specific, and genome-wide, epigenetic alterations with causal links to oncogenic cellular phenotypes. Some recent examples of cell-based high throughput chemical screening assays are presented that have been applied or have shown potential for application to epigenetic endpoints.
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PMID:A Tox21 Approach to Altered Epigenetic Landscapes: Assessing Epigenetic Toxicity Pathways Leading to Altered Gene Expression and Oncogenic Transformation In Vitro. 2858 63