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)

Although little is understood of the underlying mechanisms, there are tissue-specific responses to tumourigenic and therapeutic agents and these responses are influenced by genetic factors. Ionizing radiation is an important tumourigenic and therapeutic agent for which there is substantial evidence for such tissue-dependent and genotype-dependent responses. Because the p53 tumour suppressor protein is a major determinant of cellular responses to radiation, the present study has investigated whether modification of the p53 pathway contributes to tissue-dependent and genotype-dependent responses using inbred strains of mice. Comparison of responses in haemopoietic and epithelial cells in irradiated C57BL/6 and DBA/2 mice revealed significant differences in p53 and apoptotic responses in different cell types and in different cells of the same type, reflecting the complexity of damage responses operating in the whole organism. The data suggest that p53-mediated up-regulation of Bax is a major determinant of apoptosis in the spleen, but not in the intestine, whereas p53-mediated induction of p21(waf1) plays an anti-apoptotic role in the spleen, but not in the intestine. It is also shown that p53 stabilization and differential transactivational activities towards Bax or p21(waf1) are influenced by genetic factors that act in a tissue-specific manner. Analysis of ATM, a potential mediator of differential p53 activation, indicates that this key regulator of radiation responses is preferentially induced in epithelial cells, but is unlikely to account for genetic modification of p53 or apoptotic responses in the mouse strains studied. Polymorphisms in the p53 or DNA-PKcs genes are also unlikely to account for the genetic modifications that are reported here. There are numerous further potential modifiers of the p53 pathway, but analysis of backcross and inter-cross mice demonstrates that genes responsible for the complex modification of these in vivo responses can be identified by linkage analysis. This approach has the potential to reveal new or unexpected interactions involving the p53 pathway that determine both short-term and long-term effects of radiation exposure and the basis of tissue-specific responses and tumour susceptibility.
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PMID:Tissue-specific p53 responses to ionizing radiation and their genetic modification: the key to tissue-specific tumour susceptibility? 1459 49

Gonadectomy induces in certain inbred stains of mice adrenal hyperplasia and tumorigenesis, originating from the putative subcapsular stem/progenitor cell layer. This response is apparently triggered by the elevated post-gonadectomy levels of luteinising hormone (LH), followed by ectopic upregulation of adrenal LH/chorionic gonadotrophin (CG) receptors (Lhcgr). The clear strain dependence of this adrenal response to gonadectomy prompted us to study its genetic basis. Tumorigenic DBA/2J and non-tumorigenic C57BL/6J mice, as well as their F2 and backcrosses, were studied by whole genome linkage analysis. Gonadectomy induced similar upregulation of adrenal Lhcgr in both parental strains and their crosses, irrespective of the tumour status, indicating that ectopic expression of this receptor is not the immediate cause of tumours. Linkage analysis revealed one major significant quantitative trait locus (QTL) for the tumorigenesis on chromosome 8, modulated by epistasis with another QTL on chromosome 18. Hence, post-gonadectomy adrenal tumorigenesis in DBA/2J mice is a dominant trait, not a direct consequence of adrenal Lhcgr expression, and is driven by a complex genetic architecture. A promising candidate gene in the tumorigenesis linkage region is Sfrp1 (secreted frizzled-related protein 1), a tumour suppressor gene, which was down-regulated in the neoplastic tissue. Our findings may have relevance to the human pathogenesis of macronodular adrenal hyperplasia and postmenopausal adrenocortical tumours. A distinctly different adrenal response was observed in TG mice overexpressing LH or CG, or a constitutively activated form of the follicle-stimulating hormone receptor (Fshr). These mice developed perimedullary hyperlasia of foamy multinucleated cells, reminding of macrophages and filled with lipofuscin. Similar response was observed in TG mice overexpressing aromatase (CYP19). The cause of this response is not related to direct LH/CG action, but merely to adrenal response to chronically elevated oestrogen levels. This phenotype is reminiscent of the rare 'black adenomas' of the human adrenal cortex.
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PMID:Adrenal hyperplasia and tumours in mice in connection with aberrant pituitary-gonadal function. 1900 52