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Methylation in the p21WAF1/cip1 promoter of Apc+/−, p21+/− mice and lack of response to sulindac

Oncogene volume 24, pages 2104–2109 (2005)Cite this article

Abstract

p21WAF1/cip1 plays a critical role in regulating intestinal cell proliferation, maturation and tumorigenesis. Our previous work demonstrated that inactivation of a single p21 allele in Apc1638+/− mice was sufficient to accelerate Apc-initiated tumor formation, and that inactivation of only one p21 allele was also sufficient to abrogate duodenal tumor inhibition by sulindac, a nonsteroidal anti-inflammatory drug. To dissect the role of p21 in sulindac inhibition of intestinal tumor development in Apc1638+/− mice, we quantified p21 expression from Apc+/−, p21+/+, +/− or −/− mice fed sulindac. In Apc+/−, p21 wild-type mice fed the sulindac supplemental diet, both p21 mRNA and protein were significantly increased in the flat mucosa and tumors of the duodenum. However, p21 was not induced by sulindac in the duodenal flat mucosa and tumors of Apc+/− mice in which one or both p21 alleles had been inactivated. Further investigation revealed that the cytosine residues in a CpG cluster in the promoter region of the mouse p21 gene displayed hypermethylation in the Apc+/−, p21+/− mice. This suggested that although the p21+/− mice retained a wild-type allele, this allele was functionally modulated by hypermethylation, and that the inability of sulindac to inhibit tumor formation in Apc+/−, p21+/− mice is likely due to the inability to induce expression of the wild-type, but differentially methylated, p21 allele.

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Acknowledgements

We wish to acknowledge support of the Albert Einstein Cancer Center Core DNA-sequencing facility, and our thanks to Dr Philip Leder for providing the p21 knockout mice and to Min Zhuang for the assistance of statistic analysis. Grant support: This work was supported in part by CA96605, CA120196, CA87559, and PO1 13330 from the National Cancer Institute.

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  1. Department of Oncology, Montefiore Medical Center, Albert Einstein Cancer Center, 111 East 210th Street, Bronx, NY, 10467, USA

    WanCai Yang, Laura Bancroft & Leonard H Augenlicht

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Correspondence to WanCai Yang.

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Yang, W., Bancroft, L. & Augenlicht, L. Methylation in the p21WAF1/cip1 promoter of Apc+/−, p21+/− mice and lack of response to sulindac. Oncogene 24, 2104–2109 (2005). https://doi.org/10.1038/sj.onc.1208444

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