Bipolar Disorder and Ubiquitin Proteasome System Dysfunction: Peripheral Blood Levels of Molecules Playing a Role in Ubiquitination and Their Relationship to Sleep QualityAydιnoğlu, Yazla, Çetin
et alDiscov Med (2024) 36 (190), 2244-2252
Abstract: Bipolar disorder (BD) is a serious mood disorder, notable for its morbidity and prevalence. It ranks among the top 10 diseases globally in terms of functional impairment among affected individuals. Studies investigating neurobiological processes in the development of BD also aim to identify biological markers. Ubiquitin is a protein that is abundant in all eukaryotic cells and regulates many processes through the ubiquitin-proteasome system. It has been reported to be associated with circadian rhythm and sleep disorders. Circadian rhythm plays a key role in maintaining mood stability in individuals with BD. In this study, we investigated the peripheral levels of molecules involved in the ubiquitination process and their relationship to sleep quality in individuals with BD.Forty-nine patients with BD and 50 healthy volunteers without any psychiatric disorders were included. The Pittsburgh Sleep Quality Index, the Young Mania Rating Scale, and the Hamilton Depression Rating Scale were administered to the participants. Peripheral blood levels of proteins and enzymes that play a role in ubiquitination processes were determined by the immunosorbent assay method.TAR DNA-binding protein-43 (TDP-43) (p < 0.001), ubiquitin C-terminal hydrolase-L1 enzyme (UCH-L1) (p = 0.037), ubiquitin C-terminal hydrolase-L3 enzyme (UCH-L3) (p = 0.007), histone deacetylase I (Histone Dea-1) (p = 0.006), histone deacetylase II (Histone Dea-2) (p = 0.047), and ligase cullin-3 (p = 0.031) levels were found to be significantly lower in the BD group than in the control group, but these parameters were not associated with sleep quality scores in the BD group.Our results support the data in the literature but show that the ubiquitination process can be affected in BD patients without being associated with sleep quality.
Stem Cell Properties of Gastric Cancer Stem-Like Cells under Stress Conditions Are Regulated via the c-Fos/UCH-L3/β-Catenin AxisLee, Park, Park
et alMol Cells (2023) 46 (8), 476-485
Abstract: Gastric cancer stem-like cells (GCSCs) possess stem cell properties, such as self-renewal and tumorigenicity, which are known to induce high chemoresistance and metastasis. These characteristics of GCSCs are further enhanced by autophagy, worsening the prognosis of patients. Currently, the mechanisms involved in the induction of stemness in GCSCs during autophagy remain unclear. In this study, we compared the cellular responses of GCSCs with those of gastric cancer intestinal cells (GCICs) whose stemness is not induced by autophagy. In response to glucose starvation, the levels of β-catenin and stemness-related genes were upregulated in GCSCs, while the levels of β-catenin declined in GCICs. The pattern of deubiquitinase ubiquitin C-terminal hydrolase-L3 (UCH-L3) expression in GCSCs and GCICs was similar to that of β-catenin expression depending on glucose deprivation. We also observed that inhibition of UCH-L3 activity reduced β-catenin protein levels. The interaction between UCH-L3 and β-catenin proteins was confirmed, and it reduced the ubiquitination of β-catenin. Our results suggest that UCH-L3 induces the stabilization of β-catenin, which is required to promote stemness during autophagy activation. Also, UCH-L3 expression was regulated by c-Fos, and the levels of c-Fos increased in response to autophagy activation. In summary, our findings suggest that the inhibition of UCH-L3 during nutrient deprivation could suppress stress resistance of GCSCs and increase the survival rates of gastric cancer patients.
UCH-L3 structure and function: Insights about a promising drug targetHafez, Modather El-Awadly, Arafa
Eur J Med Chem (2022) 227, 113970
Abstract: In the past few years, researchers have shed light on the immense importance of ubiquitin in numerous regulatory pathways. The post-translational addition of mono or poly-ubiquitin molecules namely "ubiquitinoylation" is therefore pivotal to maintain the cell's vitality, maturation, differentiation, and division. Part of conserving homeostasis stems from maintaining the ubiquitin pool in the vicinity of the cell's intracellular environment; this crucial role is played by deubiquitylating enzymes (DUBs) that cleave ubiquitin molecules from target molecules. To date, they are categorized into 7 families with ubiquitin carboxyl c-terminal de-hydrolase family (UCH) as the most common and well-studied. Ubiquitin C-terminal hydrolase L (UCH-L3) is a significant protein in this family as it has been implicated in many molecular and cellular processes with its mRNA identified in a range of body tissues including the brain. It goes without saying that it manifests in maintaining health and when abnormally regulated in disease. As it is an attractive small molecule drug target, scientists have used high throughput screening (HTS) and other drug discovery methods to discover inhibitors for this enzyme for the treatment of cancer and neurodegenerative diseases. In this review we present an overview of UCH-L3 catalytic mechanism, structure, its role in DNA repair and cancer along with the inhibitors discovered so far to halt its activity.Copyright © 2021 Elsevier Masson SAS. All rights reserved.
UCH-L1 and UCH-L3 regulate the cancer stem cell-like properties through PI3 K/Akt signaling pathway in prostate cancer cellsLee, Lim, Kim
Anim Cells Syst (Seoul) (2021) 25 (5), 312-322
Abstract: Castration-resistant prostate cancer (CRPC) is a highly aggressive and advanced prostate cancer that is currently incurable with conventional therapies. The recurrence and chemotherapy-resistant properties of CRPC are attributed to prostate cancer stem cells (CSCs). On the other hand, the factors regulating the prostate CSC-like properties have not been studied extensively. Previously, ubiquitin C-terminal hydrolase-L1 (UCH-L1) and ubiquitin C-terminal hydrolase-L3 (UCH-L3) were reported to be involved in prostate cancer cell progression through the epithelial-to-mesenchymal transition (EMT) regulation. Here, the differential regulation on the CSC-like properties by UCH-L1 and UCH-L3 were identified in prostate cancer cells. The CSC-like characteristics, such as the expression of pluripotency markers, chemoresistance, and sphere-forming ability, were promoted by UCH-L1, whereas those were repressed by UCH-L3. Moreover, the modulation of CSC-like properties by UCH-L1 and UCH-L3 was through the PI3 K/Akt signaling pathway. The CSC-like properties induced by UCH-L1 overexpression or UCH-L3 depletion were suppressed by the PI3 K/Akt pathway inhibitor. In conclusion, UCH-L1 and UCH-L3 are novel regulators of the CSC-like properties and shed light on new therapeutic strategies to overcome CSCs in prostate cancers.© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
膜杰作
Star Staining
