Available online at www.sciencedirect.com Mutation Research 640 (2008) 54–73 Effect of p53 genotype on gene expression profiles in murine liver Suzanne M. Morris a,∗ , Gregory S. Akerman b , Varsha G. Desai c , Chen-an Tsai d , William H. Tolleson e , William B. Melchior Jr. e , Chien-Ju Lin f , James C. Fuscoe c , Daniel A. Casciano g , James J. Chen f a Division of Genetic and Reproductive Toxicology, National Center for Toxicological Research, US Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, United States b Toxicology Branch, Health Effects Division (7509P), US Environmental Protection Agency, 1200 Pennsylvania Avenue, NW, Washington, DC 20460, United States c Division of Systems Toxicology, National Center for Toxicological Research, US Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, United States d Biostatistics Center and Department of Public Health, China Medical University, Taichung, 40402, Taiwan e Division of Biochemical Toxicology, National Center for Toxicological Research, US Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, United States f Division of Personalized Nutrition and Medicine, National Center for Toxicological Research, US Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, United States g Dan Casciano and Associates, 47 Marcella Drive, Little Rock, AR 72233, United States Received 20 July 2007; received in revised form 30 November 2007; accepted 11 December 2007 Available online 23 December 2007 Abstract 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 ≤ 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. Published by Elsevier B.V. Keywords: Transgenic mice; p53; Microarray; Real-time quantitative PCR; Gene expression 1. Introduction The tumor suppressor protein p53 serves as one of the key regulatory elements in the maintenance of genomic integrity in mammalian cells and is involved in a multiplicity of cellular ∗ Corresponding author at: HFT-120/DGRT/NCTR, 3900 NCTR Road, Jef- ferson, AR 72079, United States. Tel.: +1 870 543 7580; fax: +1 870 543 7393. E-mail address: suzanne.morris@fda.hhs.gov (S.M. Morris). functions. P53 is also recognized as the most commonly mutated gene in human malignancies. Taken together, these factors sug- gest that the role of “guardian of the genome” ascribed to p53 may reflect its ability to reduce the effects of DNA damage to the genome and inhibit progression towards malignancy. Thus, the study of p53 function is one of the most active areas of investigation at present. One approach to studying p53 function was the development of transgenic mice in which the p53 gene was deleted by the use of targeted recombination. Although several models have 0027-5107/$ – see front matter. Published by Elsevier B.V. doi:10.1016/j.mrfmmm.2007.12.004