In the Apc1638(+/-) mouse model of intestinal
tumorigenesis, targeted inactivation of the
cyclin-dependent kinase inhibitor p21(WAF1/cip1) is highly effective in enhancing Apc-initiated
tumor formation in the intestine. Because p21(WAF1/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
beta-catenin. We found that inactivation of p21(WAF1/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 p21(WAF1/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 p27(kip1) 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 beta-catenin-Tcf4 signaling, but which may converge on common elements downstream of this signaling pathway.