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.

Abstract

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.

• Authors: W C Yang, J Mathew, A Velcich, W Edelmann, R Kucherlapati, M Lipkin, K Yang, L H Augenlicht
• Journal: Cancer research (Cancer Res) Vol. 61 Issue 2 Pg. 565-9 (Jan 15 2001) ISSN: 0008-5472 [Print] United States
• PMID: 11212250 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Adenomatous Polyposis Coli Protein
• Cdkn1a protein, mouse
• Cyclin-Dependent Kinase Inhibitor p21
• Cyclins
• Cytoskeletal Proteins
• Mucins
• Proliferating Cell Nuclear Antigen

Topics

• Adenomatous Polyposis Coli Protein
• Animals
• Apoptosis
• Cell Differentiation (genetics)
• Cell Division (genetics)
• Cyclin-Dependent Kinase Inhibitor p21
• Cyclins (genetics)
• Cytoskeletal Proteins (genetics)
• Diet (adverse effects)
• Female
• Gastrointestinal Neoplasms (etiology, genetics, pathology)
• Gene Silencing
• Genotype
• Immunohistochemistry
• Intestinal Mucosa (chemistry, metabolism, pathology)
• Male
• Mice
• Mice, Mutant Strains
• Mucins (analysis)
• Mutation
• Proliferating Cell Nuclear Antigen (analysis)
• Survival Analysis