A novel p53 mutational hotspot in skin tumors from UV-irradiated Xpc mutant mice alters transactivation functions.
A mutation in codon 122 of the mouse p53 gene resulting in a T to L amino acid substitution (T122-->L) is frequently associated with skin cancer in UV-irradiated mice that are both homozygous mutant for the nucleotide excision repair (NER) gene Xpc (Xpc(-/-)) and hemizygous mutant for the p53 gene. We investigated the functional consequences of the mouse T122-->L mutation when expressed either in mammalian cells or in the yeast Saccharomyces cerevisiae. Similar to a non-functional allele, high expression of the T122-->L allele in p53(-/-) mouse embryo fibroblasts and human Saos-2 cells failed to suppress growth. However, the T122-->L mutant p53 showed wild-type transactivation levels with Bax and MDM2 promoters when expressed in either cell type and retained transactivation of the p21 and the c-Fos promoters in one cell line. Using a recently developed rheostatable p53 induction system in yeast we assessed the T122-->L transactivation capacity at low levels of protein expression using 12 different p53 response elements (REs). Compared to wild-type p53 the T122-->L protein manifested an unusual transactivation pattern comprising reduced and enhanced activity with specific REs. The high incidence of the T122-->L mutant allele in the Xpc(-/-) background suggests that both genetic and epigenetic conditions may facilitate the emergence of particular functional p53 mutations. Furthermore, the approach that we have taken also provides for the dissection of functions that may be retained in many p53 tumor alleles.
Inga
Alberto
A
Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, NIH, PO Box 12233, Research Triangle Park, North Carolina, NC 27709, USA.
Nahari
Dorit
D
Velasco-Miguel
Susana
S
Friedberg
Errol C
EC
Resnick
Michael A
MA
D000483:Alleles; D000818:Animals; D017209:Apoptosis; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics*; D016193:G1 Phase; D016158:Genes, p53; D051379:Mice; D009154:Mutation; D012878:Skin Neoplasms / Q000235:genetics*; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D014466:Ultraviolet Rays
D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; C501002:Xpc protein, mouse