Characterization of p53 tumor suppressor pathway in mouse colon epithelial cells and azoxymethane-induced colon tumor

Date of Completion

January 2006

Keywords

Biology, Molecular

Degree

Ph.D.

Abstract

The goal of this study was to characterize p53 tumor suppressor pathway in colon-specific carcinogen azoxymethane (AOM)-induced mouse colon tumor and to assess the usefulness of this animal model to evaluate novel anti-cancer drugs. The acute exposure of mice to AOM showed no overall induction of p53-regulated genes. Subdued p53 gene activation in the colon corresponded to a drop in the expression of its transcriptional co-activator, p300. The status of p53 pathway was further analyzed using AOM-induced mouse colon tumor and the cell line (AJ02-NM0) generated from the primary tumor. Wild type p53 protein, constitutively expressed in this model, showed no detectable DNA binding activity nor did it activate p21 expression. The cell line studies revealed that p53 activity was inhibited by a constitutive interaction with Mdm2. The p53-activating p19/ARF protein did not appear to have significant effect on the standing of p53 pathway in this cell line. p53 was activated by Doxorubicin, 5-FU and the recently developed Mdm2 inhibitor Nutlin-3. Moreover, Nutlin-3 robustly activated p53 target gene expression in mouse colon tumors treated ex vivo, without significantly affecting normal mucosa. Our data suggest that specific Mdm2 inhibitors may be an effective means of treating colon cancers that retain a sequence-normal p53 gene. Overall study strongly implies that AOM-induced mouse colon tumor is extremely useful model for the evaluation of novel treatments against p53-normal colon cancer.^

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