A comparison of gene expression changes in response to diethylstilbestrol treatment in wild-type and p53+/- hemizygous knockout mice using focussed arrays.
We have investigated the hepatic response of female C57BL/6J wild-type and p53(+/-) hemizygous mice to genotoxic levels of diethylstilbestrol (DES) using cell cycle and apoptosis-focussed cDNA expression arrays. DES induced the expression of 12 genes (bad, bax, bcl-x, caspase-1, p53, cyclin D3, GADD45, p21, p15, p27, p57 and Skp1) and down-regulated the expression of eight genes (bcl-2, caspase-2, caspase-7, caspase-8, E124, iNOS, mdm2 and NFkappab1) at twofold or greater levels. Taken together, these changes were strongly reflective of the induction of apoptosis in the livers of DES-treated mice. Of those genes showing the greatest changes in response to DES, p53, p21 and p57 were expressed at 2.1, 1.7 and 1.6 times greater (respectively) in wild-type mice as compared with p53(+/-) hemizygous mice. Differences in p53, p21 and bax expression were confirmed by RT-PCR and we conclude that the compromised response of p53(+/-) mice is likely to play a central role in the earlier appearance of tumours in this model, following exposure to genotoxic carcinogens.
Salleh
Mohd Nazil
MN
Biological Chemistry, Division of Biomedical Sciences, Imperial College of Science, Technology and Medicine, Sir Alexander Fleming Building, South Kensington, London SW7 2AZ, UK.
Caldwell
John
J
Carmichael
Paul L
PL
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D004247:DNA / Q000032:analysis; D004054:Diethylstilbestrol / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D016158:Genes, p53; D006579:Heterozygote; D007274:Injections, Intraperitoneal; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D002273:Carcinogens; D012333:RNA, Messenger; D004054:Diethylstilbestrol; D004247:DNA