Impact of USP8 Gene Mutations on Protein Deregulation in Cushing Disease

Isabel Weigand, Lisanne Knobloch, Jörg Flitsch, Wolfgang Saeger, Camelia M Monoranu, Kerstin Höfner, Sabine Herterich, Roman Rotermund, Cristina L Ronchi, Michael Buchfelder, Markus Glatzel, Christian Hagel, Martin Fassnacht, Timo Deutschbein, Silviu Sbiera

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)
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Abstract

Cushing disease (CD) is a rare disorder with severe sequels and incompletely understood pathogenesis. The underlying corticotroph adenomas harbor frequently somatic mutations in the ubiquitin-specific peptidase 8 (USP8) gene. These mutations render USP8 hyperactive and prevent client proteins from degradation. Objective: To investigate the impact of USP8 mutations on proteins deregulated in CD. Design: One hundred eight pituitary adenomas (75 corticotroph [58 USP8 wild type (WT) and 17 USP8 mutated], 14 somatotroph, and 19 nonfunctioning) were investigated by immunohistochemistry. All evaluated proteins [USP8, arginine vasopressin receptor 1b and 2, corticotropinreleasing hormone receptor, cAMP response element-binding protein (CREB), p27/kip1, cyclin E, heat shock protein 90 (HSP90), orphan nuclear receptor 4, epidermal growth factor receptor, histone deacetylase 2, glucocorticoid receptor, cyclin-dependent kinase 5 and Abelson murine leukemia viral oncogene homolog 1 enzyme substrate 1] were known to be deregulated in CD. Furthermore, AtT20 cells were transfected with USP8 to investigate the expression of possible downstream proteins by immunoblot.

Original languageEnglish
Pages (from-to)2535-2546
Number of pages12
JournalJournal of Clinical Endocrinology and Metabolism
Volume104
Issue number7
Early online date7 Mar 2019
DOIs
Publication statusPublished - Jul 2019

Keywords

  • USP8 mutations
  • Cushing's disease
  • AVPR1b
  • CRHR
  • p27
  • HSP90
  • CREB
  • TR4
  • cyclinE
  • EGFR

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