Effect of p53 genotype on gene expression profiles in murine liver.
The tumor suppressor protein p53 is a key regulatory element in the cell and is regarded as the "guardian of the genome". Much of the present knowledge of p53 function has come from studies of transgenic mice in which the p53 gene has undergone a targeted deletion. In order to provide additional insight into the impact on the cellular regulatory networks associated with the loss of this gene, microarray technology was utilized to assess gene expression in tissues from both the p53(-/-) and p53(+/-) mice. Six male mice from each genotype (p53(+/+), p53(+/-), and p53(-/-)) were humanely killed and the tissues processed for microarray analysis. The initial studies have been performed in the liver for which the Dunnett test revealed 1406 genes to be differentially expressed between p53(+/+) and p53(+/-) or between p53(+/+) and p53(-/-) at the level of p < or = 0.05. Both genes with increased expression and decreased expression were identified in p53(+/-) and in p53(-/-) mice. Most notable in the gene list derived from the p53(+/-) mice was the significant reduction in p53 mRNA. In the p53(-/-) mice, not only was there reduced expression of the p53 genes on the array, but genes associated with DNA repair, apoptosis, and cell proliferation were differentially expressed, as expected. However, altered expression was noted for many genes in the Cdc42-GTPase pathways that influence cell proliferation. This may indicate that alternate pathways are brought into play in the unperturbed liver when loss or reduction in p53 levels occurs.
Morris
Suzanne M
SM
Division of Genetic and Reproductive Toxicology, National Center for Toxicological Research, US Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, United States. suzanne.morris@fda.hhs.gov
Akerman
Gregory S
GS
Desai
Varsha G
VG
Tsai
Chen-An
CA
Tolleson
William H
WH
Melchior
William B
WB
Lin
Chien-Ju
CJ
Fuscoe
James C
JC
Casciano
Daniel A
DA
Chen
James J
JJ
D000818:Animals; D020869:Gene Expression Profiling; D016158:Genes, p53; D005838:Genotype; D006579:Heterozygote; D008099:Liver; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D005810:Multigene Family; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction