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From the Department of Oncology, Montefiore Medical Center, Albert Einstein Cancer Center, Bronx, New York
In the Apc1638+/– mouse model of intestinal tumorigenesis, targeted inactivation of the cyclin-dependent kinase inhibitor p21WAF1/cip1 is highly effective in enhancing Apc-initiated tumor formation in the intestine. Because p21WAF1/cip1 plays a critical role in regulating intestinal cell proliferation, maturation, and tumorigenesis, we examined whether its inactivation would enhance tumor formation in a different mouse model of colon cancer. Therefore, we mated p21–/– mice with mice carrying a genetic deficiency of the Muc2 gene, which encodes the major gastrointestinal mucin. Muc2–/– mice develop tumors in the small and large intestine and the rectum, but in contrast to tumors in Apc1638+/– mice, this does not involve increased expression or nuclear localization of ß-catenin. We found that inactivation of p21WAF1/cip1 significantly increased the frequency and size of intestinal tumors in Muc2 knockout mice and also led to development of more invasive adenocarcinomas. This enhanced tumorigenesis significantly decreased mouse life span. Further, inactivation of p21WAF1/cip1 increased cell proliferation, decreased apoptosis, and decreased intestinal trefoil factor expression in the mucosa of both the small and large intestine. Surprisingly, reduced expression of p27kip1 was also observed in the Muc2–/–, p21+/–, and p21–/– mice. In contrast, the expression of c-myc was significantly elevated. Thus, p21 modulates the formation of tumors whose initiation does (Apc) or does not (Muc2) involve altered ß-catenin-Tcf4 signaling, but which may converge on common elements downstream of this signaling pathway.
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