Targeted inactivation of the p21(WAF1/cip1) gene enhances Apc-initiated tumor formation and the tumor-promoting activity of a Western-style high-risk diet by altering cell maturation in the intestinal mucosal.
Elimination of both alleles of the gene that encodes the cyclin kinase inhibitor p21(WAF1/cip1) increases 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 beta-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.
Yang
W C
WC
Albert Einstein Cancer Center, Bronx, New York 10467, USA.
Mathew
J
J
Velcich
A
A
Edelmann
W
W
Kucherlapati
R
R
Lipkin
M
M
Yang
K
K
Augenlicht
L H
LH
D025601:Adenomatous Polyposis Coli Protein; D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics*; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004032:Diet / Q000009:adverse effects*; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D020868:Gene Silencing; D005838:Genotype; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000737:chemistry / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009077:Mucins / Q000032:analysis; D009154:Mutation; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D016019:Survival Analysis
D025601:Adenomatous Polyposis Coli Protein; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D003598:Cytoskeletal Proteins; D009077:Mucins; D018809:Proliferating Cell Nuclear Antigen