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Tamoxifen-inducible in vivo mouse system for studying p53 tumour suppression


Fusion proteins between the hormone binding domain of a mutant mouse oestrogen receptor (ERTM) and the tumour suppressor p53 are strictly tamoxifen-dependent. To study the role of p53 in suppressing carcinogenesis in vivo protein expression of a tamoxifen-dependent domi- nant negative DN p53 ERTM construct will be targeted to specific tissues in transgenic mice. Wild type pS3 will then be functionally inactivated in target tissues by administration of tamoxifen to affected animals and spontaneous carcinogenesis will be awaited or mice will be subjected to various known carcinogenic regimes.
In a second approach, by homologous recombination in ES cells mice will be created in which one copy of wild-type p53 has been replaced with a gene encoding the tamoxifen-de- pendent p53 ERTM protein. The remaining intact p53 allele will be sporadically lost to give rise to tumours which will then be analysed towards their responsiveness to p53 tumour sup- pression by administration of tamoxifen and thereby activating the p53 ERTM protein. These investigations may provide the basis for a successful gene therapy of cancer.

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Imperial Cancer Research Fund
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44 Lincoln's Inn Fields
WC2A 3PX London
United Kingdom

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