Mouse models for the p53 R72P polymorphism mimic human phenotypes.
The p53 tumor suppressor gene contains a common single nucleotide polymorphism (SNP) that results in either an arginine or proline at position 72 of the p53 protein. This polymorphism affects the apoptotic activity of p53 but the mechanistic basis and physiologic relevance of this phenotypic difference remain unclear. Here, we describe the development of mouse models for the p53 R72P SNP using two different approaches. In both sets of models, the human or humanized p53 proteins are functional as evidenced by the transcriptional induction of p53 target genes in response to DNA damage and the suppression of early lymphomagenesis. Consistent with in vitro studies, mice expressing the 72R variant protein (p53R) have a greater apoptotic response to several stimuli compared with mice expressing the p53P variant. Molecular studies suggest that both transcriptional and nontranscriptional mechanisms may contribute to the differential abilities of the p53 variants to induce apoptosis. Despite a difference in the acute response to UV radiation, no difference in the tumorigenic response to chronic UV exposure was observed between the polymorphic mouse models. These findings suggest that under at least some conditions, the modulation of apoptosis by the R72P polymorphism does not affect the process of carcinogenesis.
Zhu
Feng
F
Department of Carcinogenesis, Science Park-Research Division, The University of Texas MD Anderson Cancer Center, Smithville, Texas 78957, USA.
Dollé
Martijn E T
ME
Berton
Thomas R
TR
Kuiper
Raoul V
RV
Capps
Carrie
C
Espejo
Alexsandra
A
McArthur
Mark J
MJ
Bedford
Mark T
MT
van Steeg
Harry
H
de Vries
Annemieke
A
Johnson
David G
DG
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects; D022202:Chromosomes, Artificial, Bacterial; D003062:Codon; D005091:Exons; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics; D023421:Models, Animal; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012878:Skin Neoplasms / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics*; D014466:Ultraviolet Rays
D003062:Codon; D015514:Oncogene Proteins, Fusion; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53