Somatic Mutations of the p53 Tumor Suppressor Gene in Experimental Neoplasia

27 May

Concurrent with the extensive work done on the somatic mutations in the p53 tumor suppressor gene in humans, a number of animal systems have been investigated in a similar manner. Fortu- nately, the gene and protein structure of p53 is conserved within the mammalian kingdom, and thus reagents can be used to some extent across species. Table 6.6 lists a number of studies in rats and mice in which mutations have been discovered and for the most part characterized as to

Figure 6.3 Proportions  of various  types of somatic  mutations  in the p53 tumor suppressor  gene in a large number of cancers [upper left, p53 (n = 1312)] and in several types of neoplasms. The numbers in parentheses  next to the type of cancer and p53 indicate the numbers of mutations.  (Adapted from Harris and Hollstein, 1993, with permission of the authors and publisher.)

specific  codons  and base changes.  Numerous  other studies have examined  the immunohis- tochemical staining of p53 in tissue sections, but since this is not an absolute method for identi- fying somatic mutations in the gene, these are not included here.

As can be noted from the table, the frequency of mutations in the various systems shown ranges from very high to less than 10% of the neoplasms examined. Since almost all of these examples are from neoplasms resulting from chemical carcinogenesis,  the sequence alterations are of significance. Interestingly, aflatoxin B1 administered to rats does not induce mutations at codon 249 (Hulla et al., 1993) such as seen in p53 from humans exposed to this carcinogen (Fig- ure 6.3). Furthermore, p53 mutations are virtually absent from mouse liver tumors, either sponta- neous or chemically induced (Kress et al., 1992a; Goodrow et al., 1992; Rumsby et al., 1994), as well as from neoplasms induced in rat liver by a peroxisome proliferator that has no known di- rect covalent interaction with DNA (Smith et al., 1993a). In addition, administration  of nickel subsulfide and iron, a mixture carcinogenic for the rat kidney, resulted in neoplasms that did not exhibit mutations in the p53 gene (Weghorst et al., 1994). Thus, for a number of chemical carcin- ogens, the p53 tumor suppressor gene is either not a target or one that is hit only in frequently, although it is possible that the p53 gene is mutated often but not selected for in these tumors.

Random Posts

Comments are closed.