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Murine models of neoplasia: functional analysis of the tumour suppressor genesRb-1 andp53

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Abstract

Loss of function of one or both of the two tumour suppressor genesp53 andRB-1 has been recognised as an important step in the development of a variety of human neoplasias for some time. By virtue of the ability to manipulate the genome of murine embryonic stem cells in culture, it has become possible to generate strains of mice which bear inactivations of the murine counterparts of these genes. This article attempts to bring together some of the many results obtained from these murine strains which are shedding light both on the normal role played by both of these genes and the consequences of their dysfunction. Surprisingly neither gene product is revealed to have an indispensable role at the level of the single cell. Hence, even though theRb-1 gene product clearly has an important role in cell cycle regulation animals constitutively deficient in this gene develop relatively normally for the first 10 days of embryogenesis. It is only at and beyond this stage of development that a requirement forRb-1 becomes clear, in the regulation of certain cell populations through control of both proliferation and apoptosis. That loss of function ofRb-1 is associated with tumorigenesis is confirmed by the development of tumours of the pituitary gland within heterozygotes. The retinas of these animals, the target organ for tumorigenesis in humanRB-1 heterozygotes, remain unaffected. The majority of mice homozygous for an inactivatingp53 mutation survive to birth, but then rapidly succumb to tumorigenesis. Heterozygotes also develop tumours, but with a delayed time course and altered spectrum. Analysis of several tissue types from the mutant animals has shownp53 to be crucial for the normal induction of apoptosis following DNA damage, and it is thought that failure of this process is a key predisposing step towards tumorigenesis within the mutant animals. Finally, studies on these and other transgenic strains have revealed interactions between pathways governed by these two genes. For example, the fate ofRb-1 deficient cells has been shown, in some tissues at least, to be dependent upon the functional status ofp53.

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    Alan R. Clarke

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Clarke, A.R. Murine models of neoplasia: functional analysis of the tumour suppressor genesRb-1 andp53 . Cancer Metast Rev 14, 125–148 (1995). https://doi.org/10.1007/BF00665796

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