title: Decoding the genetic basis of Cushing's disease: USP8 in the spotlight.
abstract: Cushing's disease (CD) arises from pituitary-dependent glucocorticoid excess due to an ACTH-secreting corticotroph tumor. Genetic hits in oncogenes and tumor suppressor genes that afflict other pituitary tumor subtypes are not found in corticotrophinomas. Recently, a somatic mutational hotspot was found in up to half of corticotrophinomas in the USP8 gene that encodes a protein that impairs the downregulation of the epidermal growth factor receptor (EGFR) and enables its constitutive signaling. EGF is an important regulator of corticotroph function and its receptor is highly expressed in Cushing's pituitary tumors, where it leads to increased ACTH synthesis in vitro and in vivo. The mutational hotspot found in corticotrophinomas hyper-activates USP8, enabling it to rescue EGFR from lysosomal degradation and ensure its stimulatory signaling. This review presents new developments in the study of the genetics of CD and focuses on the USP8-EGFR system as trigger and target of corticotroph tumorigenesis.
authors.affiliation: Department of EndocrinologyMax Planck Institute of Psychiatry, Kraepelinstrasse 10, Munich 80804, GermanyMedizinische Klinik und Poliklinik IVLudwig-Maximilians-Universität München, Munich, GermanyEndocrine and Diabetes UnitDepartment of Medicine I, University Hospital, University of Würzburg, Würzburg, GermanyDepartment of Biological SciencesTokyo Institute of Technology, 4259-B16 Nagatsuta, Midori, Yokohama 226-8501, Japan marily@mpipsykl.mpg.de makomada@bio.titech.ac.jp.
authors.forename: Marily
authors.initials: M
authors.lastname: Theodoropoulou
authors.affiliation: Department of EndocrinologyMax Planck Institute of Psychiatry, Kraepelinstrasse 10, Munich 80804, GermanyMedizinische Klinik und Poliklinik IVLudwig-Maximilians-Universität München, Munich, GermanyEndocrine and Diabetes UnitDepartment of Medicine I, University Hospital, University of Würzburg, Würzburg, GermanyDepartment of Biological SciencesTokyo Institute of Technology, 4259-B16 Nagatsuta, Midori, Yokohama 226-8501, Japan.
authors.forename: Martin
authors.initials: M
authors.lastname: Reincke
authors.affiliation: Department of EndocrinologyMax Planck Institute of Psychiatry, Kraepelinstrasse 10, Munich 80804, GermanyMedizinische Klinik und Poliklinik IVLudwig-Maximilians-Universität München, Munich, GermanyEndocrine and Diabetes UnitDepartment of Medicine I, University Hospital, University of Würzburg, Würzburg, GermanyDepartment of Biological SciencesTokyo Institute of Technology, 4259-B16 Nagatsuta, Midori, Yokohama 226-8501, Japan.
authors.forename: Martin
authors.initials: M
authors.lastname: Fassnacht
authors.affiliation: Department of EndocrinologyMax Planck Institute of Psychiatry, Kraepelinstrasse 10, Munich 80804, GermanyMedizinische Klinik und Poliklinik IVLudwig-Maximilians-Universität München, Munich, GermanyEndocrine and Diabetes UnitDepartment of Medicine I, University Hospital, University of Würzburg, Würzburg, GermanyDepartment of Biological SciencesTokyo Institute of Technology, 4259-B16 Nagatsuta, Midori, Yokohama 226-8501, Japan marily@mpipsykl.mpg.de makomada@bio.titech.ac.jp.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Komada
mesh_terms: D049913:ACTH-Secreting Pituitary Adenoma / Q000235:genetics* / Q000378:metabolism; D000236:Adenoma / Q000235:genetics* / Q000378:metabolism; D010450:Endopeptidases / Q000235:genetics* / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics* / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D006801:Humans; D047748:Pituitary ACTH Hypersecretion / Q000235:genetics* / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000235:genetics* / Q000378:metabolism
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D010450:Endopeptidases; C541534:USP8 protein, human; D043222:Ubiquitin Thiolesterase