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Circumvention and reactivation of the p53 oncogene checkpoint in mouse colon tumors.

Author	Wataru Aizu, Glenn S Belinsky, Christopher Flynn, Emily J Noonan, Colleen C Boes, Cassandra A Godman, Bindi Doshi, Prashant R Nambiar, Daniel W Rosenberg, Charles Giardina
Citation Information	Biochemical pharmacology, 72:981-91 (2006)
Keywords	Animals, Apoptosis, Azoxymethane, Carcinogens, Cell Line, Tumor, Colonic Neoplasms, Genes, p53, Imidazoles, Male, Mice, Mice, Inbred Strains, Piperazines, Proto-Oncogene Proteins c-mdm2, Tumor Suppressor Protein p53
Related Products	S7100
Pub Med ID	16949053

The p53 tumor suppressor protein is sequence-normal in azoxymethane (AOM)-induced mouse colon tumors, making them a good model for human colon cancers that retain a wild type p53 gene. Cellular localization and co-immunoprecipitation experiments using a cell line derived from an AOM-induced colon tumor (AJ02-NM(0) cells) pointed to constitutively expressed Mdm2 as being an important negative regulator of p53 in these cells. Although the Mdm2 inhibitory protein p19/ARF was expressed in AJ02-NM(0) cells, its level of expression was not sufficient for p53 activation. We tested the response of AJ02-NM(0) cells to the recently developed Mdm2 inhibitor, Nutlin-3. Nutlin-3 was found to activate p53 DNA binding in AJ02-NM(0) cells, to a level comparable to doxorubicin and 5-fluorouracil (5-FU). In addition, Nutlin-3 increased expression of the p53 target genes Bax and PERP to a greater extent than doxorubicin or 5-FU, and triggered a G2/M phase arrest in these cells, compared to a G1 arrest triggered by doxorubicin and 5-FU. The differences in the cellular response may be related to differences in the kinetics of p53 activation and/or its post-translational modification status. In an ex vivo experiment, Nutlin-3 was found to activate p53 target gene expression and apoptosis in AOM-induced tumor tissue, but not in normal adjacent mucosa. Our data indicate that Mdm2 inhibitors may be an effective means of selectively targeting colon cancers that retain a sequence-normal p53 gene while sparing normal tissue and that the AOM model is an appropriate model for the preclinical development of these drugs.