TY - JOUR
T1 - Targeted inactivation of the p21WAF1/cip1gene enhances Apc-initiated tumor formation and the tumor-promoting activity of a Western-style high-risk diet by altering cell maturation in the intestinal mucosa
AU - Wan Cai, Yang C.
AU - Mathew, Joseph
AU - Velcich, Anna
AU - Edelmann, Winfried
AU - Kucherlapati, Raju
AU - Lipkin, Martin
AU - Yang, Kan
AU - Augenlicht, Leonard H.
PY - 2001/1/15
Y1 - 2001/1/15
N2 - Elimination of both alleles of the gene that encodes the cyclin kinase inhibitor p21WAF1/cip1increases the frequency and size of intestinal tumors in Apc1638+/-mice that inherit a mutant allele of the Apc gene, and intermediate effects are seen if a single p21 allele is inactivated. The increased tumor formation is associated with altered cell maturation in the intestinal mucosa of the p21-deficient mice - increased cell proliferation, and decreased apoptosis, and goblet cell differentiation - that is also a function of p21 gene dosage. Moreover, a Western-style diet that mimics principal risk factors for colon cancer (high fat and phosphate, low calcium and vitamin D) accelerates tumor formation in Apc1638+/-mice, and the loss of a single or both p21 alleles is additive with the tumor-promoting effects of this diet, resulting in more and larger tumors, and a highly significant decrease in survival time. Thus, p21 normally suppresses Apc-initiated tumor formation and is haplo-insufficient in this regard. This is consistent with recent reports that Apc initiates tumor formation by up-regulating c-myc expression through altered β-catenin-Tcf signaling and that c-myc then up-regulates cdk4, whose activity is inhibited by p21. Decreased expression of p21 is also a marker of poor prognosis in patients, and the data presented suggest that dietary alterations in patients undergoing treatment for colon cancer might be highly effective in improving outcome.
AB - Elimination of both alleles of the gene that encodes the cyclin kinase inhibitor p21WAF1/cip1increases the frequency and size of intestinal tumors in Apc1638+/-mice that inherit a mutant allele of the Apc gene, and intermediate effects are seen if a single p21 allele is inactivated. The increased tumor formation is associated with altered cell maturation in the intestinal mucosa of the p21-deficient mice - increased cell proliferation, and decreased apoptosis, and goblet cell differentiation - that is also a function of p21 gene dosage. Moreover, a Western-style diet that mimics principal risk factors for colon cancer (high fat and phosphate, low calcium and vitamin D) accelerates tumor formation in Apc1638+/-mice, and the loss of a single or both p21 alleles is additive with the tumor-promoting effects of this diet, resulting in more and larger tumors, and a highly significant decrease in survival time. Thus, p21 normally suppresses Apc-initiated tumor formation and is haplo-insufficient in this regard. This is consistent with recent reports that Apc initiates tumor formation by up-regulating c-myc expression through altered β-catenin-Tcf signaling and that c-myc then up-regulates cdk4, whose activity is inhibited by p21. Decreased expression of p21 is also a marker of poor prognosis in patients, and the data presented suggest that dietary alterations in patients undergoing treatment for colon cancer might be highly effective in improving outcome.
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M3 - Article
C2 - 11212250
AN - SCOPUS:0035863515
SN - 0008-5472
VL - 61
SP - 565
EP - 569
JO - Cancer research
JF - Cancer research
IS - 2
ER -