A genetic model for colorectal tumorigenesis

Mutations in the p53 tumour-suppressor gene are the most frequently observed genetic lesions in human cancers. To investigate the role of the p53 gene in mammalian development and tumorigenesis, a null mutation was introduced into the gene by homologous recombination in murine embryonic stem cells. Mice homozygous for the null allele appear normal but are prone to the spontaneous development of a variety of neoplasms by 6 months of age. These observations indicate that a normal p53 gene is dispensable for embryonic development, that its absence predisposes the animal to neoplastic disease, and that an oncogenic mutant form of p53 is not obligatory for the genesis of many types of tumours.

Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours

The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53

The cell cycle is composed of a series of steps which can be negatively or positively regulated by various factors. Chief among the negative regulators is the p53 protein. Alteration or inactivation of p53 by mutation, or by its interactions with oncogene products of DNA tumour viruses, can lead to cancer. These mutations seem to be the most common genetic change in human cancers.

The p53 tumour suppressor gene

https://www.cell.com/cell/pdf/0092-8674(92)90644-R.pdf

The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation

p53 is a cellular phosphoprotein of short half-life (t1/2;) which is present at elevated levels in cells transformed by various stimuli including viruses, chemicals and radiation1–5. p53 forms specific stable complexes with simian virus 40 (SV40) large-T itntigen and an adenovirus Elb protein of relative molecular mass (Mr) 57,000 (refs 4–7). A number of reports have associated p53 with cell proliferation8–11, and p53 complementary DNA expression constructs immortalize primary cells in vitro12 and render them sensitive to transformation by an activated ras oncogene12–14. We have examined the biological properties of a set of p53 expression constructs, and report here that cellular immortalization by a wild-type p53 cDNA gene is conditional upon the promoter/enhancer construction used, but that p53 can extend cellular lifespan by a second distinct mechanism involving rearrangements of the coding sequence which give rise to stable protein products. Cells immortalized by one of these mutants are refractory to subsequent transformation by a ras oncogene, indicating that cellular immortalization and ras cooperation are separate activities.

The cellular oncogene p53 can be activated by mutagenesis.

Malignant transformation of primary cells requires at least two distinct and characteristic alterations in cellular behaviour. The first, cellular immortality, can be induced by chemical carcinogens or by cloned oncogenes such as polyoma large T (ref. 4), adenovirus early region 1A (E1A) or the oncogene from avian (MC29) myelocytomatosis virus, v-myc. Cells whose in vitro life-span has been extended by these procedures can be fully transformed by transfection with oncogenes belonging to a different complementation group, including genes of the ras family, adenovirus E1b and polyoma virus middle T (refs 4, 5). The unstable cellular phosphoprotein p53 is frequently present at elevated levels in transformed cells and is stabilized by the formation of complexes with simian virus 40 (SV40) large T or adenovirus E1b 57K protein. Although several reports have associated p53 with cell proliferation, its role remains obscure. We have cloned complementary DNA sequences encoding murine p53 and report here that transfection of p53 expression constructs into cells of finite lifespan in vitro results in cellular immortality and susceptibility to transformation by a ras oncogene.

Cellular immortalization by a cDNA clone encoding the transformation-associated phosphoprotein p53.

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The cellular oncogene p53 can be activated by mutagenesis.

Cellular immortalization by a cDNA clone encoding the transformation-associated phosphoprotein p53.