Mutational and nonmutational activation of p21ras in rat colonic azoxymethane-induced tumors: effects on mitogen-activated protein kinase, cyclooxygenase-2, and cyclin D1.

摘要: Azoxymethane (AOM)-induced colonic carcinogenesis involves a number of mutations, including those in the K-ras gene and CTNNB1, that codes for beta-catenin. Prior vitro studies have also demonstrated wild type p21(K-ras) can be activated by epigenetic events. We identified 15 mutations 14 84 AOM-induced tumors three independent methods. By single strand conformational polymorphism, we observed 22 68 exon 3 CTNNB1. A highly sensitive method was then used to measure p21ras activation levels. All assayed possessing had significantly higher levels (8.8 +/- 1.5%; n = 13) compared with control colon (3.7 0.4; 6; P < 0.05) or without such (4.2 0.4%; 70; 0.05). Among wild-type K-ras, there subset (18 70) (8.0 0.9%; 18) colons. In four examined p21ras, increased c-erbB-2 receptor expression decreased Ras-GAP expression. contrast, only one eight ras nonactivated these alterations. Mitogen-activated protein kinase (MAPK) cyclooxygenase-2 (COX-2) were mutated their counterparts. Although beta-catenin did not alter COX-2 MAPK activity, either cyclin D1 but p21-ras, enhanced. Thus, spectrum changes MAPK, COX-2, is distinct among nonmutational p21ras.