PMID:17875695

Citation	Blanc, V, Henderson, JO, Newberry, RD, Xie, Y, Cho, SJ, Newberry, EP, Kennedy, S, Rubin, DC, Wang, HL, Luo, J and Davidson, NO (2007) Deletion of the AU-rich RNA binding protein Apobec-1 reduces intestinal tumor burden in Apc(min) mice. Cancer Res. 67:8565-73
Abstract	The RNA-specific cytidine deaminase apobec-1 is an AU-rich RNA binding protein that binds the 3' untranslated region (UTR) of cyclooxygenase-2 (Cox-2) mRNA and stabilizes its turnover in vitro. Cox-2 overexpression accompanies intestinal adenoma formation in both humans and mice. Evidence from both genetic deletion studies as well as from pharmacologic inhibition has implicated Cox-2 in the development of intestinal adenomas in experimental animals and in adenomas and colorectal cancer in humans. Here, we show that small intestinal adenoma formation is dramatically reduced in compound Apc(min/+) apobec-1(-/-) mice when compared with the parental Apc(min/+) strain. This reduced tumor burden was found in association with increased small intestinal apoptosis and reduced proliferation in small intestinal crypt-villus units from compound Apc(min/+) apobec-1(-/-) mice. Intestinal adenomas from compound Apc(min/+) apobec-1(-/-) mice showed a <2-fold increase in Cox-2 mRNA abundance and reduced prostaglandin E(2) content compared with adenomas from the parental Apc(min/+) strain. In addition, there was reduced expression in adenomas from compound Apc(min/+) apobec-1(-/-) mice of other mRNAs (including epidermal growth factor receptor, peroxisome proliferator-activated receptor delta, prostaglandin receptor EP4, and c-myc), each containing the apobec-1 consensus binding site within their 3'-UTR. Adenovirus-mediated apobec-1 introduction into HCA-7 (colorectal cancer) cells showed a dose-dependent increase in Cox-2 protein and stabilization of endogenous Cox-2 mRNA. These findings suggest that deletion of apobec-1, by modulating expression of AU-rich RNA targets, provides an important mechanism for attenuating a dominant genetic restriction point in intestinal adenoma formation.
Links	PubMed Online version:10.1158/0008-5472.CAN-07-1593
Keywords	Adenoma/enzymology; Adenoma/genetics; Animals; Colorectal Neoplasms/genetics; Colorectal Neoplasms/metabolism; Cyclooxygenase 2/biosynthesis; Cyclooxygenase 2/genetics; Cytidine Deaminase/biosynthesis; Cytidine Deaminase/deficiency; Cytidine Deaminase/genetics; Genes, APC; Humans; Intestinal Neoplasms/enzymology; Intestinal Neoplasms/genetics; Intestine, Small/pathology; Male; Mice; Mice, Inbred C57BL; RNA, Messenger/biosynthesis; RNA, Messenger/genetics
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