The Gene of the Ubiquitin-Specific Protease 8 Is Frequently Mutated in Adenomas Causing Cushing's Disease

Pérez-Rivas, Luis Gustavo; Theodoropoulou, Marily; Ferraú, Francesco; Nusser, Clara; Kawaguchi, Kohei; Stratakis, Constantine A.; Faucz, Fábio R.; Wildemberg, Luiz Eduardo; Assié, Guillaume; Beschorner, Rudi; Dimopoulou, Christina; Buchfelder, Michael; Popović, Vera; Berr, Christina M.; Tóth, Miklós; Ardisasmita, Arif Ibrahim; Honegger, Jürgen; Bertherat, Jérôme; Gadelha, Mônica R.; Beuschlein, Felix; Stalla, Günter; Komada, Masayuki; Korbonits, Márta; Reincke, Martín

doi:10.1210/jc.2015-1453

Cited by 180 publications

(241 citation statements)

References 38 publications

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“…Previously-reported USP8 mutants loose binding to 14-3-3 proteins, undergo cleavage adjacent to the 14-3-3 binding motif to the 90-and 40-kDa fragments, and the 40-kDa fragment (C40) acquires high DUB activity (9,11). Since the functions of three of the seven USP8 mutants identified in this study (S718F, S719P, and S718_P720delinsT) had not been determined, we performed a functional analysis.…”

Section: Functional Analysis Of Usp8 Mutationsmentioning

confidence: 97%

“…S718_P720delinsT was a novel mutation. Others (S718del, P720R, S719P, S718F, P720Q, and P720_D721del) have been previously identified (9,10,11). USP8 mRNA levels were measured using qRT-PCR to determine whether the expression levels of USP8 differed between the USP8 mutants and the WT.…”

Section: European Journal Of Endocrinologymentioning

confidence: 99%

“…These mutations potentially lead to the deubiquitination of EGFR, thereby increasing EGFR signaling, which has been implicated in corticotroph tumorigenesis. Furthermore, in vitro studies revealed that USP8 mutations enhanced the promoter activity of the gene encoding proopiomelanocortin (POMC) through stabilized EGFR signaling, which may explain ACTH hypersecretion in patients with CD (9,10,11). These findings have raised the question as to whether USP8 mutations are associated with the clinical features of CD such as tumor aggressiveness, ACTH hypersecretion, surgical remission rate, and drug susceptibility to the dopamine agonist cabergoline and somatostatin analog pasireotide (12,13), as well as the alkylating agent temozolomide, which is used in the treatment of aggressive pituitary adenomas and carcinomas (2,14,15,16).…”

Section: Introductionmentioning

confidence: 99%

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The USP8 mutational status may predict drug susceptibility in corticotroph adenomas of Cushing's disease

Hayashi

Inoshita

Kawaguchi

et al. 2016

European Journal of Endocrinology

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137

156

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Context: Somatic mutations in the ubiquitin-specific peptidase USP8 gene were recently detected in one-to two-third(s) of corticotroph adenomas of Cushing's disease (CD). These mutations may lead to the deubiquitination of EGFR, thereby increasing EGFR signaling, which has been implicated in ACTH hypersecretion. Objective: Our objective was to determine the impact of USP8 mutations on the clinicopathological features of CD. Subjects and methods: USP8 mutations as well as clinicopathological characteristics were examined in 60 corticotroph adenomas including 15 Crooke's cell adenomas (CCAs), a rare histological variant presenting with generally aggressive behavior, using qRT-PCR and/or immunohistochemistry. Results: USP8 mutations were exclusively detected in women, except for one case, with a prevalence of 42.2% in non-CCA and 13.3% in CCA (overall 35%). Clinically well-behaved presentations including microadenoma and curative resection were more common in mutated cases. The expression of EGFR was not associated with the mutation status. In contrast, mutated tumors expressed significantly higher levels of POMC, SSTR5, and MGMT. Conclusions: Microadenomas that strongly express POMC were common among mutated tumors, which may lead to the mechanisms by which very small adenomas secrete excess ACTH to present overt CD. While USP8 mutations were less likely to enhance tumorous ACTH hypersecretion via EGFR-mediated activation, the presence of USP8 mutations may predict favorable responses to the somatostatin analog pasireotide, which exhibits high affinity for SSTR5. In contrast, non-mutated aggressive tumors such as CCA may respond better to the alkylating agent temozolomide because of their significantly weak expression of MGMT.

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Section: Functional Analysis Of Usp8 Mutationsmentioning

confidence: 97%

Section: European Journal Of Endocrinologymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The USP8 mutational status may predict drug susceptibility in corticotroph adenomas of Cushing's disease

Hayashi

Inoshita

Kawaguchi

et al. 2016

European Journal of Endocrinology

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137

156

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“…Indeed, this revealed recurrent mutations in the USP8 gene that encodes a deubiquitinase (Perez-Rivas et al 2015, Reincke et al 2015. Although USP8 could have many different substrates (Ge et al 2015), current analyses indicate that corticotroph adenomas with USP8 mutations have persistent EGF signaling.…”

Section: Defective Signaling In Cushing's Diseasementioning

confidence: 84%

60 YEARS OF POMC: Transcriptional and epigenetic regulation of POMC gene expression

Drouin

2016

Journal of Molecular Endocrinology

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Expression of the pro-opiomelanocortin (POMC) gene integrates numerous inputs that reflect the developmental history of POMC-expressing cells of the pituitary and hypothalamus, as well as their critical role in the endocrine system. These inputs are integrated at specific regulatory sequences within the promoter and pituitary or hypothalamic enhancers of the POMC locus. Investigations of developmental mechanisms and transcription factors (TFs) responsible for pituitary activation of POMC transcription led to the discovery of the Pitx factors that have critical roles in pituitary development and striking patterning functions in embryonic development. Terminal differentiation of the two pituitary POMC lineages, the corticotrophs and melanotrophs, is controlled by Tpit; mutations of the human TPIT gene cause isolated adrenocorticotrophic hormone deficiency. Intermediate lobe and melanotroph identity is provided by the pioneer TF Pax7 that remodels chromatin to reveal a new repertoire of enhancers for Tpit action. Many signaling pathways regulate POMC transcription including activation by hypothalamic corticotrophin-releasing hormone acting through the orphan nuclear receptors of the Nur family and feedback repression by glucocorticoids and their glucocorticoid receptor. TFs of the basic helix-loop-helix, Smad, Stat, Etv, and nuclear factor-B families also mediate signals for control of POMC transcription. Whereas most of these regulatory processes are conserved in different species, there are also notable differences between specific targets for regulation of the human compared with mouse POMC genes.

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“…Perez-Rivas et al (39) demonstrated that somatic mutations comprising p.718Ser>Pro, Ser718del, p.720Pro>Gln, and p.720Pro>Arg in USP8 diminished EGFR ubiquitination and induced the activity of the POMC promoter. Ma et al (40) reported the significant clinical relevance of three somatic mutations (c.CTC2151-2153del/p.S718del, c.C2159G/p.…”

Section: Ubiquitin-specific Peptidase 8 (Usp8) Mutationmentioning

confidence: 99%

Gene mutations in Cushing's disease

Xiong

2016

Biomedical Reports

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Abstract. Cushing's disease (CD) is a severe (and potentially fatal) disease caused by adrenocorticotropic hormone (ACTH)-secreting adenomas of the pituitary gland (often termed pituitary adenomas). The majority of ACTH-secreting corticotroph tumors are sporadic and CD rarely appears as a familial disorder, thus, the genetic mechanisms underlying CD are poorly understood. Studies have reported that various mutated genes are associated with CD, such as those in menin 1, aryl hydrocarbon receptor-interacting protein and the nuclear receptor subfamily 3 group C member 1. Recently it was identified that ubiquitin-specific protease 8 mutations contribute to CD, which was significant towards elucidating the genetic mechanisms of CD. The present study reviews the associated gene mutations in CD patients.

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The Gene of the Ubiquitin-Specific Protease 8 Is Frequently Mutated in Adenomas Causing Cushing's Disease

Abstract: USP8 is frequently mutated in adenomas causing Cushing's disease, especially in those from female adult patients diagnosed at a younger age.

Cited by 180 publications

References 38 publications

The USP8 mutational status may predict drug susceptibility in corticotroph adenomas of Cushing's disease

The USP8 mutational status may predict drug susceptibility in corticotroph adenomas of Cushing's disease

60 YEARS OF POMC: Transcriptional and epigenetic regulation of POMC gene expression

Gene mutations in Cushing's disease

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