4.7 Article

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

Journal

BIOCHEMICAL PHARMACOLOGY
Volume 72, Issue 8, Pages 981-991

Publisher

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2006.07.009

Keywords

colon cancer; p19/ARF; p53; Mdm2; Nutlin-3; azoxymethane; mouse model

Funding

  1. NCI NIH HHS [CA-81428] Funding Source: Medline

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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-NM0 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-NM0 cells, its level of expression was not sufficient for p53 activation. We tested the response of AJ02-NM0 cells to the recently developed Mdm2 inhibitor, Nutlin-3. Nutlin-3 was found to activate p53 DNA binding in AJ02-NM0 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 pS3 gene while sparing normal tissue and that the AOM model is an appropriate model for the preclinical development of these drugs. (c) 2006 Elsevier Inc. All rights reserved.

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