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Lack of Ubiquitin Specific Protease 8 (USP8) Mutations in Canine Corticotroph Pituitary Adenomas

Please always quote using this URN: urn:nbn:de:bvb:20-opus-148020
  • Purpose Cushing’s disease (CD), also known as pituitary-dependent hyperadrenocorticism, is caused by adrenocorticotropic hormone (ACTH)-secreting pituitary tumours. Affected humans and dogs have similar clinical manifestations, however, the incidence of the canine disease is thousand-fold higher. This makes the dog an obvious model for studying the pathogenesis of pituitary-dependent hyperadrenocorticism. Despite certain similarities identified at the molecular level, the question still remains whether the two species have a sharedPurpose Cushing’s disease (CD), also known as pituitary-dependent hyperadrenocorticism, is caused by adrenocorticotropic hormone (ACTH)-secreting pituitary tumours. Affected humans and dogs have similar clinical manifestations, however, the incidence of the canine disease is thousand-fold higher. This makes the dog an obvious model for studying the pathogenesis of pituitary-dependent hyperadrenocorticism. Despite certain similarities identified at the molecular level, the question still remains whether the two species have a shared oncogenetic background. Recently, hotspot recurrent mutations in the gene encoding for ubiquitin specific protease 8 (USP8) have been identified as the main driver behind the formation of ACTH-secreting pituitary adenomas in humans. In this study, we aimed to verify whether USP8 mutations also play a role in the development of such tumours in dogs. Methods Presence of USP8 mutations was analysed by Sanger and PCR-cloning sequencing in 38 canine ACTH-secreting adenomas. Furthermore, the role of USP8 and EGFR protein expression was assessed by immunohistochemistry in a subset of 25 adenomas. Results None of the analysed canine ACTH-secreting adenomas presented mutations in the USP8 gene. In a subset of these adenomas, however, we observed an increased nuclear expression of USP8, a phenotype characteristic for the USP8 mutated human tumours, that correlated with smaller tumour size but elevated ACTH production in those tumours. Conclusions Canine ACTH-secreting pituitary adenomas lack mutations in the USP8 gene suggesting a different genetic background of pituitary tumourigenesis in dogs. However, elevated nuclear USP8 protein expression in a subset of tumours was associated with a similar phenotype as in their human counterparts, indicating a possible end-point convergence of the different genetic backgrounds in the two species. In order to establish the dog as a useful animal model for the study of CD, further comprehensive studies are needed.show moreshow less

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Author: Silviu Sbiera, Marianna A. Tryfonidou, Isabel Weigand, Guy C. M. Grinwis, Bart Broeckx, Sabine Herterich, Bruno Allolio, Timo Deutschbein, Martin Fassnacht, Björn P. Meij
URN:urn:nbn:de:bvb:20-opus-148020
Document Type:Journal article
Faculties:Medizinische Fakultät / Medizinische Klinik und Poliklinik I
Language:English
Parent Title (English):Plos One
Year of Completion:2016
Volume:11
Issue:12
Pagenumber:e0169009
Source:PLoS ONE 11(12): e0169009. https://doi.org/10.1371/journal.pone.0169009
DOI:https://doi.org/10.1371/journal.pone.0169009
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Tag:adenomas; cytoplasmic staining; dogs; mutation; nuclear staining; pituitary adenomas; pituitary gland; protein expression
Release Date:2017/06/09
Collections:Open-Access-Publikationsfonds / Förderzeitraum 2016
Licence (German):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung