Monica Hollstein, David Sidransky, Bert Vogelstein, and Curtis C. Harris
WHEREAS ANEUPLOIDY IS ALMOST ALWAYS FOUND IN human cancers , the most common cancer-related genetic change known at the gene level is p53 mutation . The normal allele of this autosomal gene encodes a 53-kD nuclear phosphoprotein involved in the control of cell proliferation, and various mutant alleles with single base substitutions code for proteins that have altered growth regulatory properties [3-9]. In addition to point mutations, allelic loss, rearrangements, and deletions of the p53 gene have been detected in human tumors [10-15]. These aberrations, together with alterations of oncogenes and other tumor suppressor genes, make up the mutational network leading to malignancy. In this review, we focus on the patterns of base substitution mutations in the p53 gene observed in human cancers and their etiological implications. An analysis of base substitution mutations is of interest for two reasons.
First, because endogenous and exogenous mutagens generate specific kinds of base substitutions at certain preferred sites [16-18], the p53 mutational spectrum in tumors may provide information about the origins of the mutations that give rise to human cancers. Second, the positions of tumor mutations in the p53 gene sequence define regions of the p53 protein that are like to be essential for its biological activities and for its interaction with other cellular and viral proteins. Location of Mutations Within p53 Biochemical features of the p53 protein that may be relevant to the location of mutations are (i) the presence of several domains well conserved in evolution  and (ii) the ability to form complexes with viral and cellular proteins such as the simian virus 40 (SV40) large T antigen, the adenovirus 5 Elb protein, the E6 proteins of human papillomavirus 16 and 18 [20-23], and the 70-kD family of heat shock proteins (hsc70) .
In addition, some p53 mutants lose transcriptional activation potency and lose their ability to bind DNA [25-27]. Sequencing of the p53 gene in mammals, amphibians, birds, and fish has revealed five highly conserved domains, four of which fal within exons 5 through 8 : domain ii (codons 117 to 142), domain iii (codons 171 to 181), domain iv (codons 234 to 258), and domain v (codons 270 to 286). Domains iii, iv, and v are included in the two binding regions for SV40 large T antigen , whereas mutations at various positions between codons 66 and 228 result in a mutant protein able to bind to hsc70 [3, 29, 30]. Ninety-eight percent of the 280 base substitution mutations in this review fall within a 600-base pair region of the p53 gene product (codons 110 to 307, Fig. 1).
This sequence encompasses exons 5 through 8, where most of the evolutionarily conserved amino acids are concentrated. Mutation analyses have been confined principally to these exons. Studies that included outlying exons suggest that tumor mutations outside exons 5 through 8 are rare [31-36]; nevertheless, they may be underrepresented in this review. Uninvolved tissues from the patients were tested in many of the cancer cases with p53 mutations in this…
Source Citation (MLA 8 th Edition)
Hollstein, Monica, et al. “p53 mutations in human cancers.” Science, vol. 253, no. 5015, 1991, p. 49+. Academic OneFile, Accessed 6 Feb. 2017.