Elevated cyclooxygenase-2 levels in Min mouse adenomas
| Autor: | Raymond N. DuBois, Laura W. Lamps, A. Radhika, T Zhang, Lillian B. Nanney, Christopher S. Williams, C Luongo, R D Beauchamp |
|---|---|
| Rok vydání: | 1996 |
| Předmět: |
Adenoma
Gene isoform Pathology medicine.medical_specialty Genes APC Blotting Western Nonsense mutation Biology Polymerase Chain Reaction Germline Mice Germline mutation Intestinal Neoplasms medicine Animals Northern blot Gene Messenger RNA Hepatology Gastroenterology Blotting Northern medicine.disease Immunohistochemistry Molecular biology Isoenzymes Mice Inbred C57BL Cyclooxygenase 2 Prostaglandin-Endoperoxide Synthases |
| Zdroj: | Gastroenterology. 111:1134-1140 |
| ISSN: | 0016-5085 |
| Popis: | Background & Aims: Mutations in the APC gene result C57BL/6J mice were treated with ethylnitrosourea and in an increased propensity to develop intestinal neopla- bred for transmission of germline mutations. A line was sia; however, a complete understanding of the mecha- developed that had multiple intestinal neoplasms (Min). 3 nisms resulting in tumor formation has remained elu- These mice exhibited a phenotype similar to FAP in sive. Min mice possess a mutation in the APC gene humans. Specifically, they developed numerous intestinal and display a neoplastic phenotype similar to that ob- polyps, with a subpopulation exhibiting a neoplastic phe- served in familial adenomatous polyposis coli in hu- notype that was inherited in a fully penetrant autosomal- mans. Cyclooxygenase (COX) inhibitors decrease tu- dominant fashion. Linkage studies revealed that germline mor multiplicity in the Min mouse intestine. The transmission of a mutant allele of the APC gene was present study was designed to determine if there was tightly linked with the multiple intestinal neoplasia phe- an increase in COX-2 in adenomas harvested from Min notype. 4 Subsequently, it was shown that a germline mouse intestine. Methods: COX-2 messenger RNA lev- nonsense mutation in the APC gene was strongly corre- els were determined by Northern blots and reverse- transcription polymerase chain reactions of B6 Min 1 lated with this phenotype. 5 Additional studies have re- 129 mouse-derived tumors. Protein levels and localiza- vealed that a second inactivating mutation in the normal tion were determined by Western blots and immunohis- allele of the APC gene results in adenoma formation. 6,7 tochemical staining. Results: The Northern blots re- This is consistent with Knudson's hypothesis, which vealed an approximately threefold increase in the level states that at least two separate events are required for of COX-2 messenger RNA in Min mouse adenoma com- tumor formation. pared with normal mucosa. COX-2 protein levels in ade- Two cyclooxygenase (COX) isoforms have been identi- nomatous tissues were also approximately threefold fied, which will be referred to as COX-1 and COX-2 in higher compared with normal mucosa from the same this report. COX-1 is expressed constitutively in a num- mouse. Immunohistochemical staining with a mono- ber of cell types, whereas COX-2 is inducible by a variety specific COX-2 antibody confirmed that increases in of factors including cytokines, growth factors, and tumor COX-2 immunoreactivity were restricted to dysplastic |
| Databáze: | OpenAIRE |
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