Deletion of the AU-rich RNA binding protein Apobec-1 reduces intestinal tumor burden in Apc(min) mice.

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.

• Authors: Valerie Blanc, Jeffrey O Henderson, Rodney D Newberry, Yan Xie, Soo-Jin Cho, Elizabeth P Newberry, Susan Kennedy, Deborah C Rubin, Hanlin L Wang, Jianyang Luo, Nicholas O Davidson
• Journal: Cancer research (Cancer Res) Vol. 67 Issue 18 Pg. 8565-73 (Sep 15 2007) ISSN: 0008-5472 [Print] United States
• PMID: 17875695 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• RNA, Messenger
• Cyclooxygenase 2
• APOBEC-1 Deaminase
• APOBEC1 protein, human
• Apobec1 protein, mouse
• Cytidine Deaminase

Topics

• APOBEC-1 Deaminase
• Adenoma (enzymology, genetics)
• Animals
• Colorectal Neoplasms (genetics, metabolism)
• Cyclooxygenase 2 (biosynthesis, genetics)
• Cytidine Deaminase (biosynthesis, deficiency, genetics)
• Genes, APC
• Humans
• Intestinal Neoplasms (enzymology, genetics)
• Intestine, Small (pathology)
• Male
• Mice
• Mice, Inbred C57BL
• RNA, Messenger (biosynthesis, genetics)