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A Novel Hypomorphic Apex1 Mouse Model Implicates Apurinic/Apyrimidinic Endonuclease 1 in Oxidative DNA Damage Repair in Gastric Epithelial Cells.
Rios-Covian, David; Butcher, Lindsay D; Ablack, Amber L; den Hartog, Gerco; Matsubara, Mason T; Ly, Hong; Oates, Andrew W; Xu, Guorong; Fisch, Kathleen M; Ahrens, Eric T; Toden, Shusuke; Brown, Corrie C; Kim, Kenneth; Le, Dzung; Eckmann, Lars; Dhar, Bithika; Izumi, Tadahide; Ernst, Peter B; Crowe, Sheila E.
Afiliação
  • Rios-Covian D; Center for Veterinary Sciences and Comparative Medicine, Division of Comparative Pathology and Medicine, Department of Pathology, University of California, San Diego, La Jolla, California, USA.
  • Butcher LD; Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
  • Ablack AL; Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
  • den Hartog G; Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
  • Matsubara MT; Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
  • Ly H; Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
  • Oates AW; Center for Veterinary Sciences and Comparative Medicine, Division of Comparative Pathology and Medicine, Department of Pathology, University of California, San Diego, La Jolla, California, USA.
  • Xu G; Center for Computational Biology & Bioinformatics, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
  • Fisch KM; Center for Computational Biology & Bioinformatics, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
  • Ahrens ET; Department of Radiology, University of California, San Diego, La Jolla, California, USA.
  • Toden S; Molecular Stethoscope, Inc., San Diego, California, USA.
  • Brown CC; Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, Georgia, USA.
  • Kim K; La Jolla Institute for Immunology, La Jolla, California, USA.
  • Le D; Center for Veterinary Sciences and Comparative Medicine, Division of Comparative Pathology and Medicine, Department of Pathology, University of California, San Diego, La Jolla, California, USA.
  • Eckmann L; Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
  • Dhar B; Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky, USA.
  • Izumi T; Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky, USA.
  • Ernst PB; Center for Veterinary Sciences and Comparative Medicine, Division of Comparative Pathology and Medicine, Department of Pathology, University of California, San Diego, La Jolla, California, USA.
  • Crowe SE; Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
Antioxid Redox Signal ; 38(1-3): 183-197, 2023 01.
Article em En | MEDLINE | ID: mdl-35754343
ABSTRACT

Aims:

Though best known for its role in oxidative DNA damage repair, apurinic/apyrimidinic endonuclease 1 (APE1) is a multifunctional protein that regulates multiple host responses during oxidative stress, including the reductive activation of transcription factors. As knockout of the APE1-encoding gene, Apex1, is embryonically lethal, we sought to create a viable model with generalized inhibition of APE1 expression.

Results:

A hypomorphic (HM) mouse with decreased APE1 expression throughout the body was generated using a construct containing a neomycin resistance (NeoR) cassette knocked into the Apex1 site. Offspring were assessed for APE1 expression, breeding efficiency, and morphology with a focused examination of DNA damage in the stomach. Heterozygotic breeding pairs yielded 50% fewer HM mice than predicted by Mendelian genetics. APE1 expression was reduced up to 90% in the lungs, heart, stomach, and spleen. The HM offspring were typically smaller, and most had a malformed tail. Oxidative DNA damage was increased spontaneously in the stomachs of HM mice. Further, all changes were reversed when the NeoR cassette was removed. Primary gastric epithelial cells from HM mice differentiated more quickly and had more evidence of oxidative DNA damage after stimulation with Helicobacter pylori or a chemical carcinogen than control lines from wildtype mice. Innovation A HM mouse with decreased APE1 expression throughout the body was generated and extensively characterized.

Conclusion:

The results suggest that HM mice enable studies of APE1's multiple functions throughout the body. The detailed characterization of the stomach showed that gastric epithelial cells from HM were more susceptible to DNA damage. Antioxid. Redox Signal. 38, 183-197.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Estresse Oxidativo / Reparo do DNA Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2023 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Estresse Oxidativo / Reparo do DNA Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2023 Tipo de documento: Article