Deletion of the AU-rich RNA binding protein Apobec-1 reduces intestinal tumor burden in Apc(min) mice.
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.
Blanc
Valerie
V
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Henderson
Jeffrey O
JO
Newberry
Rodney D
RD
Xie
Yan
Y
Cho
Soo-Jin
SJ
Newberry
Elizabeth P
EP
Kennedy
Susan
S
Rubin
Deborah C
DC
Wang
Hanlin L
HL
Luo
Jianyang
J
Davidson
Nicholas O
NO
D000071479:APOBEC-1 Deaminase; D000236:Adenoma / Q000201:enzymology* / Q000235:genetics; D000818:Animals; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics; D003564:Cytidine Deaminase / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D017491:Genes, APC; D006801:Humans; D007414:Intestinal Neoplasms / Q000201:enzymology* / Q000235:genetics; D007421:Intestine, Small / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics
D012333:RNA, Messenger; D051546:Cyclooxygenase 2; D000071479:APOBEC-1 Deaminase; C000605089:APOBEC1 protein, human; C000605090:Apobec1 protein, mouse; D003564:Cytidine Deaminase