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

Gastroenterology. 2004 Oct;127(4):1139-49. doi: 10.1053/j.gastro.2004.06.022.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3' Untranslated Regions
  • APOBEC-1 Deaminase
  • Animals
  • Cyclooxygenase 2
  • Cytidine Deaminase / physiology*
  • Gamma Rays
  • Gene Expression Regulation, Enzymologic*
  • Imidazoles / pharmacology
  • Intestinal Mucosa / metabolism
  • Intestines / radiation effects*
  • Isoenzymes / genetics*
  • Lipopolysaccharides / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinases / physiology
  • Prostaglandin-Endoperoxide Synthases / genetics*
  • Pyridines / pharmacology
  • RNA, Messenger / analysis
  • Radiation Injuries / prevention & control*
  • Stem Cells / radiation effects
  • p38 Mitogen-Activated Protein Kinases


  • 3' Untranslated Regions
  • Imidazoles
  • Isoenzymes
  • Lipopolysaccharides
  • Pyridines
  • RNA, Messenger
  • Cyclooxygenase 2
  • Prostaglandin-Endoperoxide Synthases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • APOBEC-1 Deaminase
  • Apobec1 protein, mouse
  • Cytidine Deaminase
  • 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole