||5R01CA076573-03 Interpret this number
||City Of Hope/Beckman Research Institute
||Tumorigenicity of Different P53 Missense Mutations
DESCRIPTION (Adapted from the Investigator's Abstract): Most amino acid
substitutions in the central domain of the p53 protein impart increased
tumorigenic potential, somatic selective advantage, to the host mutant
somatic cell lineage. If this tumorigenic potential varies considerably
from one codon to the next, then the p53 mutational spectrum in the tumor
data base will be selection driven. If the tumorigenic potential varies
little from one codon to the next, then the p53 mutation spectrum in the
tumor data base will be mutagenesis driven and correlated with patterns of
mutagen accessibility and lesion repair rates along the p53 gene. To test
the relative contributions of these two effects, we will prepare three
databases, one from the tumor database (selection bias for tumorigenicity),
one of base substitutions fixed during vertebrate evolution of the active
p53 gene (selection bias against tumorigenicity) and one of base
substitutions which were fixed in p53 pseudogenes (unbiased selection). To
measure the effect of selection on the pattern of base substitutions sampled
into these three p53 databases, we will apply two novel selection-sensitive
analytical tools. These tools are based on properties of the genetic code
and measure the average magnitude of the protein perturbation imparted by a
base change. Preliminary results indicate that the codon-to-codon
variations of mutation frequency in the p53 tumor database are mutagenesis
driven. They also show that for mCpG->TpG transitions accumulated during
vertebrate evolution, the putative the mC->G transition usually involves the
C on the transcribed strand rather than the one on the nontranscribed strand
because the former situation on the average effects a less drastic protein
On the origin of p53 G:C --> T:A transversions in lung cancers.
, Rodin A.S.
Mutation research, 2002-10-31; 508(1-2), p. 1-19.
Human lung cancer and p53: the interplay between mutagenesis and selection.
, Rodin A.S.
Proceedings of the National Academy of Sciences of the United States of America, 2000-10-24; 97(22), p. 12244-9.
Strand asymmetry of CpG transitions as indicator of G1 phase-dependent origin of multiple tumorigenic p53 mutations in stem cells.
, Rodin A.S.
Proceedings of the National Academy of Sciences of the United States of America, 1998-09-29; 95(20), p. 11927-32.