scholarly journals Ubiquitin-Specific Protease 8 Mutant Corticotrope Adenomas Present Unique Secretory and Molecular Features and Shed Light on the Role of Ubiquitylation on ACTH Processing

2019 ◽  
Vol 110 (1-2) ◽  
pp. 119-129 ◽  
Author(s):  
Antonella Sesta ◽  
Maria Francesca Cassarino ◽  
Mariarosa Terreni ◽  
Alberto G. Ambrogio ◽  
Laura Libera ◽  
...  
Keyword(s):  
Protein Degradation ◽  
Pituitary Adenomas ◽  
Expression Profiles ◽  
Primary Cultures ◽  
Acth Secretion ◽  
Specific Protease ◽  
Ubiquitin Proteasome ◽  
Ubiquitin Specific Protease ◽  
Acth Secreting

Background: Somatic mutations in the ubiquitin-specific protease 8 (USP8) gene have recently been shown to occur in ACTH-secreting pituitary adenomas, thus calling attention to the ubiquitin system in corticotrope adenomas. Objectives: Assess the consequences of USP8 mutations and establish the role of ubiquitin on ACTH turnover in human ACTH-secreting pituitary adenomas. Methods: USP8 mutation status was established in 126 ACTH-secreting adenomas. Differences in ACTH secretion and POMC expression from adenoma primary cultures and in microarray gene expression profiles from archival specimens were sought according to USP8 sequence. Ubiquitin/ACTH coimmunoprecipitation and incubation with MG132, a proteasome inhibitor, were performed in order to establish whether ubiquitin plays a role in POMC/ACTH degradation in corticotrope adenomas. Results: USP8 mutations were identified in 29 adenomas (23%). Adenomas presenting USP8 mutations secreted greater amounts of ACTH and expressed POMC at higher levels compared to USP wild-type specimens. USP8 mutant adenomas were also more sensitive to modulation by CRH and dexamethasone in vitro. At microarray analysis, genes associated with endosomal protein degradation and membrane components were downregulated in USP8 mutant adenomas as were AVPR1B, IL11RA, and PITX2. Inhibition of the ubiquitin-proteasome pathway increased ACTH secretion and POMC itself proved a target of ubiquitylation, independently of USP8 sequence status. Conclusions: Our study has shown that USP8 mutant ACTH-secreting adenomas present a more “typical” corticotrope phenotype and reduced expression of several genes associated with protein degradation. Further, ubiquitylation is directly involved in intracellular ACTH turnover, suggesting that the ubiquitin-proteasome system may represent a target for treatment of human ACTH-secreting adenomas.

scholarly journals Ubiquitin-Specific Protease 25 Aggravates Acute Pancreatitis and Acute Pancreatitis-Related Multiple Organ Injury by Destroying Tight Junctions Through Activation of The STAT3 Pathway

2022 ◽  
Vol 9 ◽  
Author(s):  
Zhengru Liu ◽  
Mingming Qi ◽  
Shan Tian ◽  
Qian Yang ◽  
Jian Liu ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Tight Junctions ◽  
Multiple Organ ◽  
Organ Injury ◽  
Pancreatic Acinar Cells ◽  
Stat3 Pathway ◽  
Specific Protease ◽  
Ubiquitin Specific Protease ◽  
Multiple Organ Injury

Ubiquitin-specific protease 25 (USP25) plays an important role in inflammation and immunity. However, the role of USP25 in acute pancreatitis (AP) is still unclear. To evaluate the role of USP25 in AP, we conducted research on clinical AP patients, USP25wild-type(WT)/USP25 knockout (USP25−/−) mice, and pancreatic acinar cells. Our results showed that serum USP25 concentration was higher in AP patients than in healthy controls and was positively correlated with disease severity. AP patients’ serum USP25 levels after treatment were significantly lower than that at the onset of AP. Moreover, USP25 expression was upregulated in cerulein-induced AP in mice, while USP25 deficiency attenuates AP and AP-related multiple organ injury. In vivo and in vitro studies showed that USP25 exacerbates AP by promoting the release of pro-inflammatory factors and destroying tight junctions of the pancreas. We showed that USP25 aggravates AP and AP-related multiple organ injury by activating the signal transducer and activator of transcription 3 (STAT3) pathway. Targeting the action of USP25 may present a potential therapeutic option for treating AP.

scholarly journals The targetable role of herpes virus-associated ubiquitin-specific protease (HAUSP) in p190 BCR-ABL leukemia

2016 ◽  
Vol 12 (5) ◽  
pp. 3123-3126 ◽  
Author(s):  
Giovanna Carrà ◽  
Cristina Panuzzo ◽  
Sabrina Crivellaro ◽  
Deborah Morena ◽  
Riccardo Taulli ◽  
...  
Keyword(s):  
Herpes Virus ◽  
Specific Protease ◽  
Ubiquitin Specific Protease ◽  
Herpès Virus

Proteomics analysis reveals the role of ubiquitin specific protease (USP47) in Epithelial to Mesenchymal Transition (EMT) induced by TGFβ2 in breast cells

2020 ◽  
Vol 219 ◽  
pp. 103734 ◽  
Author(s):  
Virgínia Campos Silvestrini ◽  
Carolina Hassibe Thomé ◽  
Daniele Albuquerque ◽  
Camila de Souza Palma ◽  
Germano Aguiar Ferreira ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Proteomics Analysis ◽  
Mesenchymal Transition ◽  
Specific Protease ◽  
Breast Cells ◽  
Ubiquitin Specific Protease

scholarly journals Mitotane reduces human and mouse ACTH-secreting pituitary cell viability and function

2013 ◽  
Vol 218 (3) ◽  
pp. 275-285 ◽  
Author(s):  
Erica Gentilin ◽  
Federico Tagliati ◽  
Massimo Terzolo ◽  
Matteo Zoli ◽  
Marcello Lapparelli ◽  
...  
Keyword(s):  
Cell Viability ◽  
Cell Line ◽  
Primary Cultures ◽  
Pituitary Cell ◽  
Therapeutic Window ◽  
Adrenocortical Function ◽  
Acth Secretion ◽  
And Function ◽  
Acth Secreting ◽  
Human And Mouse

Medical therapy for Cushing's disease (CD) is currently based on agents mainly targeting adrenocortical function. Lately, pituitary-directed drugs have been developed, with limited efficacy. Mitotane, a potent adrenolytic drug, has been recently investigated for the treatment of CD, but the direct pituitary effects have not been clarified so far. The aim of our study was to investigate whether mitotane may affect corticotroph function and cell survival in the mouse pituitary cell line AtT20/D16v-F2 and in the primary cultures of human ACTH-secreting pituitary adenomas, as an in vitro model of pituitary corticotrophs. We found that in the AtT20/D16v-F2 cell line and in primary cultures, mitotane reduces cell viability by inducing caspase-mediated apoptosis and reduces ACTH secretion. In the AtT20/D16v-F2 cell line, mitotane reduces Pomc expression and blocks the stimulatory effects of corticotropin-releasing hormone on cell viability, ACTH secretion, and Pomc expression. These effects were apparent at mitotane doses greater than those usually necessary for reducing cortisol secretion in Cushing's syndrome, but still in the therapeutic window for adrenocortical carcinoma treatment. In conclusion, our results demonstrate that mitotane affects cell viability and function of human and mouse ACTH-secreting pituitary adenoma cells. These data indicate that mitotane could have direct pituitary effects on corticotroph cells.

EXPRESSION AND ROLE OF TYPE 1 AND 2 ISOFORMS OF UBIQUITIN-SPECIFIC PROTEASE 14 IN HUMAN PANCREATIC CANCER

Pancreas ◽  
2006 ◽  
Vol 33 (4) ◽  
pp. 471
Author(s):  
T. Ishiwata ◽  
K. Cho ◽  
S. Ishiwata ◽  
Y. Fujiwata ◽  
T. Fujii ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Human Pancreatic Cancer ◽  
Specific Protease ◽  
Ubiquitin Specific Protease

scholarly journals Allosteric switch regulates protein–protein binding through collective motion

2016 ◽  
Vol 113 (12) ◽  
pp. 3269-3274 ◽  
Author(s):  
Colin A. Smith ◽  
David Ban ◽  
Supriya Pratihar ◽  
Karin Giller ◽  
Maria Paulat ◽  
...  
Keyword(s):  
Collective Motion ◽  
Protein Domain ◽  
Allosteric Coupling ◽  
Allosteric Communication ◽  
Binding Interface ◽  
Specific Protease ◽  
Ubiquitin Specific Protease ◽  
Promising Avenue

Many biological processes depend on allosteric communication between different parts of a protein, but the role of internal protein motion in propagating signals through the structure remains largely unknown. Through an experimental and computational analysis of the ground state dynamics in ubiquitin, we identify a collective global motion that is specifically linked to a conformational switch distant from the binding interface. This allosteric coupling is also present in crystal structures and is found to facilitate multispecificity, particularly binding to the ubiquitin-specific protease (USP) family of deubiquitinases. The collective motion that enables this allosteric communication does not affect binding through localized changes but, instead, depends on expansion and contraction of the entire protein domain. The characterization of these collective motions represents a promising avenue for finding and manipulating allosteric networks.

Ghrelin Stimulates Adrenocorticotrophic Hormone (ACTH) Secretion by Human ACTH-Secreting Pituitary Adenomas In Vitro

2007 ◽  
Vol 19 (3) ◽  
pp. 208-212 ◽  
Author(s):  
F. Pecori Giraldi ◽  
L. G. Bucciarelli ◽  
A. Saccani ◽  
M. Scacchi ◽  
S. Pesce ◽  
...  
Keyword(s):  
Pituitary Adenomas ◽  
Adrenocorticotrophic Hormone ◽  
Acth Secretion ◽  
Acth Secreting

scholarly journals Mutation and Expression Analysis of Corticotropin-Releasing Factor 1 Receptor in Adrenocorticotropin-Secreting Pituitary Adenomas1

1998 ◽  
Vol 83 (9) ◽  
pp. 3327-3331
Author(s):  
K. D. Dieterich ◽  
E. D. Gundelfinger ◽  
D. K. Lüdecke ◽  
H. Lehnert
Keyword(s):  
Expression Analysis ◽  
Cushing’S Disease ◽  
Pituitary Adenomas ◽  
Messenger Rna ◽  
Corticotropin Releasing Factor ◽  
Cushing's Disease ◽  
Receptor Regulation ◽  
R Gene ◽  
Acth Secreting

The present study was designed to investigate a possible role of CRF1 receptors (CRF1-R) in the pathogenesis of Cushing’s disease. ACTH-secreting pituitary adenomas and nonsecreting pituitary adenomas have been analyzed for mutations in the CRF1-R gene by PCR and sequencing and been compared with the sequences of normal anterior pituitaries. No mutations affecting the CRF1-R protein have been found in all tumors analyzed. However, we found a significant overexpression of the CRF1-R messenger RNA in ACTH-secreting pituitary adenomas vs. inactive adenomas and normal pituitaries. We conclude that mutations of the CRF1-R are unlikely to be involved in Cushing’s disease. We suggest that the overexpression of the CRF1-R messenger RNA may be related to a disturbed receptor regulation in ACTH-secreting pituitary adenomas.

scholarly journals The role of USP7 in the Shoc2 - ERK1/2 signaling axis and Noonan-like syndrome with loose anagen hair (NSLAH)

2021 ◽  
Author(s):  
Patricia Wilson ◽  
Lina Abdelmoti ◽  
Rebecca Norcross ◽  
Eun Ryoung Jang ◽  
Malathy Palayam ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Pathway Activation ◽  
Signaling Axis ◽  
Specific Protease ◽  
Anagen Hair ◽  
Ubiquitin Specific Protease ◽  
Regulatory Feedback Loop ◽  
Organismal Development ◽  
Fine Tune

The ERK1/2 signaling pathway is critical in organismal development and tissue morphogenesis. Deregulation of this pathway leads to congenital abnormalities with severe developmental dysmorphisms. The core ERK1/2 cascade relies on scaffold proteins such as Shoc2 to guide and fine-tune its signals. Mutations in shoc2 lead to the development of the pathology termed Noonan-like Syndrome with Loose Anagen Hair (NSLAH). However, the mechanisms underlying the functions of Shoc2 and its contributions to disease progression remain unclear. Here we show that ERK1/2 pathway activation triggers the interaction of Shoc2 with the ubiquitin-specific protease USP7. We identify that in the Shoc2 module USP7 functions as a molecular “switch” that controls the E3 ligase HUWE1 and the HUWE1-induced regulatory feedback loop. We also demonstrate that disruption of Shoc2-USP7 binding leads to aberrant activation of the Shoc2-ERK1/2 axis. Importantly, our studies reveal a possible role for USP7 in the pathogenic mechanisms underlying NSLAH extending our understanding of how ubiquitin-specific proteases regulate intracellular signaling.

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