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Mutational and Nonmutational Activation of p21^ras in Rat Colonic Azoxymethane-induced Tumors: Effects on Mitogen-activated Protein Kinase, Cyclooxygenase-2, and Cyclin D1¹

Departments of Medicine and Pathology [Y. Z., J. H.], University of Chicago, Chicago, Illinois 60637 [Y. Z., J. H.], and Department of Medicine [F. C. v. L., N. V., G. R. B.], University of California, San Diego, California 92093 [M. B., S. K., R. K. W., L. N., S. S., T. A. B.]

Azoxymethane (AOM)-induced colonic carcinogenesis involves a number of mutations, including those in the K-ras gene and CTNNB1, that codes for ß-catenin. Prior in vitro studies have also demonstrated that wild type p21^K-ras can be activated by epigenetic events. We identified 15 K-ras mutations in 14 of 84 AOM-induced colonic tumors by three independent methods. By single strand conformational polymorphism, we also observed mutations in 22 of 68 tumors in exon 3 of CTNNB1. A highly sensitive method was then used to measure p21^ras activation levels. All tumors assayed possessing K-ras mutations had significantly higher p21^ras activation levels (8.8 ± 1.5%; n = 13) compared with that of control colon (3.7 ± 0.4; n = 6; P < 0.05) or tumors without such mutations (4.2 ± 0.4%; n = 70; P < 0.05). Among tumors with wild-type K-ras, there was a subset of tumors (18 of 70) that had significantly higher p21^ras activation levels (8.0 ± 0.9%; n = 18) compared with control colons. In three of four tumors examined with activated wild-type p21^ras, we observed increased c-erbB-2 receptor expression and decreased Ras-GAP expression. In contrast, only one of eight tumors examined with wild-type ras and nonactivated p21^ras demonstrated these alterations. Mitogen-activated protein kinase (MAPK) activation and cyclooxygenase-2 (COX-2) expression were increased in tumors with mutated or activated wild-type p21^ras, compared with their nonactivated counterparts. Although ß-catenin mutations did not alter COX-2 expression or MAPK activity, mutations in either K-ras or ß-catenin significantly increased cyclin D1 expression. In contrast, in tumors with wild-type but activated p21^ras, cyclin D1 expression was not enhanced. Thus, the spectrum of changes in MAPK, COX-2, and cyclin D1 is distinct among tumors with ras or ß-catenin mutations or nonmutational activation of p21^ras.

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