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Gastroenterology. 2004 Oct;127(4):1139-49.

Apobec-1 protects intestine from radiation injury through posttranscriptional regulation of cyclooxygenase-2 expression.

Author information

1
Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA. sanant@im.wustl.edu

Abstract

BACKGROUND & AIMS:

This study aimed to determine the role of the RNA binding protein apobec-1 in radioprotection of the intestine.

METHODS:

Apobec-1-deleted mice (APOBEC-1(-/-)) and wild-type controls were treated with 12 Gy of whole-body gamma-irradiation in a cesium irradiator. The number of surviving intestinal crypts was assessed 3.5 days after irradiation by using a clonogenic assay. Cyclooxygenase-2 messenger RNA and protein expression were determined by real-time polymerase chain reaction and Western blot, respectively. RNA stability was studied by examining the turnover of a chimeric transcript containing the cyclooxygenase-2 3' untranslated region cloned downstream of luciferase complementary DNA. Apobec-1 binding to the cyclooxygenase-2 3' untranslated region was studied by electrophoretic mobility shift and UV crosslinking assays.

RESULTS:

After gamma-irradiation, the survival of intestinal stem cells decreased significantly in APOBEC-1(-/-) mice. In wild-type mice treated with lipopolysaccharide before gamma-irradiation, intestinal stem cells were protected by marked increases in prostaglandin E 2 mediated by cyclooxygenase-2. No such effect was observed in the APOBEC-1(-/-) mice. The mechanism of this radioprotective effect involves the binding of apobec-1 to AU-rich sequences in the first 60 nucleotides of the 3' untranslated region of cyclooxygenase-2. Upon binding to the AU-rich sequences, apobec-1 stabilizes cyclooxygenase-2 messenger RNA. This stabilization process does not seem to be mediated by p38 mitogen-activated protein kinase pathways.

CONCLUSIONS:

Lipopolysaccharide increases intestinal stem cell survival through apobec-1-mediated regulation of cyclooxygenase-2 messenger RNA stability.

PMID:
15480992
[Indexed for MEDLINE]

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