The therapeutic potential of deubiquitinating enzyme inhibitors

2010 ◽  
Vol 38 (1) ◽  
pp. 137-143 ◽  
Author(s):  
Frédéric Colland
Keyword(s):  
Anticancer Agents ◽  
Enzyme Inhibitors ◽  
Therapeutic Potential ◽  
Ubiquitin Proteasome System ◽  
Cellular Protein ◽  
Deubiquitinating Enzymes ◽  
Promising Alternative ◽  
Mantle Cell ◽  
Ubiquitin Proteasome ◽  
Ubiquitin Conjugation

Proteases play a key role in various pathological processes and several protease inhibitors are already available for treatment. DUBs (deubiquitinating enzymes) constitute one of the largest classes of human proteases and are key effectors of the ubiquitin–proteasome system. This pathway regulating cellular protein turnover has been implicated in the pathogenesis of many human diseases, including neurodegenerative disorders, viral diseases and cancer. The therapeutic efficacy of the proteasome inhibitor Velcade® (bortezomib) for treating multiple myeloma and mantle cell lymphoma establishes this system as a valid target for cancer treatment. A promising alternative to targeting the proteasome itself would be to target the upstream, ubiquitin conjugation/deconjugation system, to generate more specific, less toxic anticancer agents. Advances in small molecule-based inhibitors specifically targeting DUBs are presented in this review.

Targeting Protein Degradation in Cancer Treatment

2020 ◽  
Vol 14 ◽  
Author(s):  
Imane Bjij ◽  
Ismail Hdoufane ◽  
Mahmoud Soliman ◽  
Menče Najdoska-Bogdanov ◽  
Driss Cherqaoui
Keyword(s):  
Protein Degradation ◽  
Therapeutic Potential ◽  
Ubiquitin Proteasome System ◽  
Degradation Pathway ◽  
Cellular Protein ◽  
Cellular Level ◽  
Cancerous Cell ◽  
Promising Target ◽  
Anti Cancer ◽  
Ubiquitin Proteasome

: The ubiquitin proteasome system (UPS) is a crucial protein degradation pathway that involves several enzymes to maintain cellular protein homeostasis. This system has emerged as a major drug target against certain types of cancer as a disruption at the cellular level of UPS enzyme components forces the transformation of normal cell into cancerous cell. Although enormous advancements have been achieved in the understanding of tumorigenesis, efficient cancer therapy remains a goal towards alleviating this serious health issue. Since UPS has become a promising target for anticancer therapies, herein we provide comprehensive review of the ubiquitin proteasome system as a significant process for protein degradation. Herein, the anti-cancer therapeutic potential of this pathway is also discussed.

scholarly journals Implications of FBXW7 in Neurodevelopment and Neurodegeneration: Molecular Mechanisms and Therapeutic Potential

2021 ◽  
Vol 15 ◽  
Author(s):  
Yu Yang ◽  
Xuan Zhou ◽  
Xinpeng Liu ◽  
Ruying Song ◽  
Yiming Gao ◽  
...  
Keyword(s):  
Neurodegenerative Disorders ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Ubiquitin Proteasome System ◽  
Cellular Protein ◽  
Protein Homeostasis ◽  
Potential Therapeutic Target ◽  
Cellular Processes ◽  
Wide Range ◽  
Ubiquitin Proteasome

The ubiquitin-proteasome system (UPS) mediated protein degradation is crucial to maintain quantitive and functional homeostasis of diverse proteins. Balanced cellular protein homeostasis controlled by UPS is fundamental to normal neurological functions while impairment of UPS can also lead to some neurodevelopmental and neurodegenerative disorders. Functioning as the substrate recognition component of the SCF-type E3 ubiquitin ligase, FBXW7 is essential to multiple aspects of cellular processes via targeting a wide range of substrates for proteasome-mediated degradation. Accumulated evidence shows that FBXW7 is fundamental to neurological functions and especially implicated in neurodevelopment and the nosogenesis of neurodegeneration. In this review, we describe general features of FBXW7 gene and proteins, and mainly present recent findings that highlight the vital roles and molecular mechanisms of FBXW7 in neurodevelopment such as neurogenesis, myelination and cerebral vasculogenesis and in the pathogenesis of some typical neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease. Additionally, we also provide a prospect on focusing FBXW7 as a potential therapeutic target to rescue neurodevelopmental and neurodegenerative impairment.

scholarly journals Unstructured Biology of Proteins from Ubiquitin-Proteasome System: Roles in Cancer and Neurodegenerative Diseases

Biomolecules ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 796 ◽  
Author(s):  
Kundlik Gadhave ◽  
Prateek Kumar ◽  
Shivani Kapuganti ◽  
Vladimir Uversky ◽  
Rajanish Giri
Keyword(s):  
Intrinsically Disordered Protein ◽  
Intrinsic Disorder ◽  
Ubiquitin Proteasome System ◽  
Cellular Protein ◽  
26S Proteasome ◽  
Deubiquitinating Enzymes ◽  
Intrinsically Disordered ◽  
Anti Cancer ◽  
Ubiquitin Proteasome ◽  
Dependent Protein

The 26S proteasome is a large (~2.5 MDa) protein complex consisting of at least 33 different subunits and many other components, which form the ubiquitin proteasomal system (UPS), an ATP-dependent protein degradation system in the cell. UPS serves as an essential component of the cellular protein surveillance machinery, and its dysfunction leads to cancer, neurodegenerative and immunological disorders. Importantly, the functions and regulations of proteins are governed by the combination of ordered regions, intrinsically disordered protein regions (IDPRs) and molecular recognition features (MoRFs). The structure–function relationships of UPS components have not been identified completely; therefore, in this study, we have carried out the functional intrinsic disorder and MoRF analysis for potential neurodegenerative disease and anti-cancer targets of this pathway. Our report represents the presence of significant intrinsic disorder and disorder-based binding regions in several UPS proteins, such as extraproteasomal polyubiquitin receptors (UBQLN1 and UBQLN2), proteasome-associated polyubiquitin receptors (ADRM1 and PSMD4), deubiquitinating enzymes (DUBs) (ATXN3 and USP14), and ubiquitinating enzymes (E2 (UBE2R2) and E3 (STUB1) enzyme). We believe this study will have implications for the conformation-specific roles of different regions of these proteins. This will lead to a better understanding of the molecular basis of UPS-associated diseases.

scholarly journals A Nut for Every Bolt: Subunit-Selective Inhibitors of the Immunoproteasome and Their Therapeutic Potential

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1929
Author(s):  
Eva M. Huber ◽  
Michael Groll
Keyword(s):  
Cell Cycle Progression ◽  
Therapeutic Potential ◽  
Cell Signalling ◽  
Selective Inhibition ◽  
Ubiquitin Proteasome System ◽  
Cellular Processes ◽  
Chemical Structures ◽  
Phase Ii Clinical Trials ◽  
Ubiquitin Proteasome ◽  
Recent Trends

At the heart of the ubiquitin–proteasome system, the 20S proteasome core particle (CP) breaks down the majority of intracellular proteins tagged for destruction. Thereby, the CP controls many cellular processes including cell cycle progression and cell signalling. Inhibitors of the CP can suppress these essential biological pathways, resulting in cytotoxicity, an effect that is beneficial for the treatment of certain blood cancer patients. During the last decade, several preclinical studies demonstrated that selective inhibition of the immunoproteasome (iCP), one of several CP variants in mammals, suppresses autoimmune diseases without inducing toxic side effects. These promising findings led to the identification of natural and synthetic iCP inhibitors with distinct chemical structures, varying potency and subunit selectivity. This review presents the most prominent iCP inhibitors with respect to possible scientific and medicinal applications, and discloses recent trends towards pan-immunoproteasome reactive inhibitors that cumulated in phase II clinical trials of the lead compound KZR-616 for chronic inflammations.

scholarly journals Role of Ubiquitin Ligases and the Proteasome in Oncogenesis: Novel Targets for Anticancer Therapies

2013 ◽  
Vol 31 (9) ◽  
pp. 1231-1238 ◽  
Author(s):  
Lindsey N. Micel ◽  
John J. Tentler ◽  
Peter G. Smith ◽  
Gail S. Eckhardt
Keyword(s):  
Cell Cycle ◽  
Anticancer Agents ◽  
Cell Cycle Control ◽  
Ubiquitin Proteasome System ◽  
Cellular Regulation ◽  
Ubiquitin Chain ◽  
Key Enzyme ◽  
Ubiquitin Proteasome ◽  
Enzyme Families ◽  
And Function

The ubiquitin proteasome system (UPS) regulates the ubiquitination, and thus degradation and turnover, of many proteins vital to cellular regulation and function. The UPS comprises a sequential series of enzymatic processes using four key enzyme families: E1 (ubiquitin-activating enzymes), E2 (ubiquitin-carrier proteins), E3 (ubiquitin-protein ligases), and E4 (ubiquitin chain assembly factors). Because the UPS is a crucial regulator of the cell cycle, and abnormal cell-cycle control can lead to oncogenesis, aberrancies within the UPS pathway can result in a malignant cellular phenotype and thus has become an attractive target for novel anticancer agents. This article will provide an overall review of the mechanics of the UPS, describe aberrancies leading to cancer, and give an overview of current drug therapies selectively targeting the UPS.

scholarly journals Noncoding RNA MaIL1 is an integral component of the TLR4–TRIF pathway

2020 ◽  
Vol 117 (16) ◽  
pp. 9042-9053 ◽  
Author(s):  
Marina Aznaourova ◽  
Harshavardhan Janga ◽  
Stephanie Sefried ◽  
Andreas Kaufmann ◽  
Jens Dorna ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Noncoding Rna ◽  
Signal Transduction Pathway ◽  
Ubiquitin Proteasome System ◽  
Lavage Fluid ◽  
Cellular Protein ◽  
Type I ◽  
Toll Like Receptor 4 ◽  
Ubiquitin Proteasome ◽  
Highly Correlated

RNA has been proposed as an important scaffolding factor in the nucleus, aiding protein complex assembly in the dense intracellular milieu. Architectural contributions of RNA to cytosolic signaling pathways, however, remain largely unknown. Here, we devised a multidimensional gradient approach, which systematically locates RNA components within cellular protein networks. Among a subset of noncoding RNAs (ncRNAs) cosedimenting with the ubiquitin–proteasome system, our approach unveiled ncRNA MaIL1 as a critical structural component of the Toll-like receptor 4 (TLR4) immune signal transduction pathway. RNA affinity antisense purification–mass spectrometry (RAP-MS) revealed MaIL1 binding to optineurin (OPTN), a ubiquitin-adapter platforming TBK1 kinase. MaIL1 binding stabilized OPTN, and consequently, loss of MaIL1 blunted OPTN aggregation, TBK1-dependent IRF3 phosphorylation, and type I interferon (IFN) gene transcription downstream of TLR4. MaIL1 expression was elevated in patients with active pulmonary infection and was highly correlated with IFN levels in bronchoalveolar lavage fluid. Our study uncovers MaIL1 as an integral RNA component of the TLR4–TRIF pathway and predicts further RNAs to be required for assembly and progression of cytosolic signaling networks in mammalian cells.

scholarly journals Advances in Deubiquitinating Enzyme Inhibition and Applications in Cancer Therapeutics

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1579 ◽  
Author(s):  
Ainsley Mike Antao ◽  
Apoorvi Tyagi ◽  
Kye-Seong Kim ◽  
Suresh Ramakrishna
Keyword(s):  
Protein Interactions ◽  
Cancer Therapeutics ◽  
Ubiquitin Proteasome System ◽  
Deubiquitinating Enzyme ◽  
Protein Protein Interactions ◽  
Deubiquitinating Enzymes ◽  
Cellular Functions ◽  
E3 Ligases ◽  
Ubiquitin Proteasome ◽  
Target Cancer

Since the discovery of the ubiquitin proteasome system (UPS), the roles of ubiquitinating and deubiquitinating enzymes (DUBs) have been widely elucidated. The ubiquitination of proteins regulates many aspects of cellular functions such as protein degradation and localization, and also modifies protein-protein interactions. DUBs cleave the attached ubiquitin moieties from substrates and thereby reverse the process of ubiquitination. The dysregulation of these two paramount pathways has been implicated in numerous diseases, including cancer. Attempts are being made to identify inhibitors of ubiquitin E3 ligases and DUBs that potentially have clinical implications in cancer, making them an important target in the pharmaceutical industry. Therefore, studies in medicine are currently focused on the pharmacological disruption of DUB activity as a rationale to specifically target cancer-causing protein aberrations. Here, we briefly discuss the pathophysiological and physiological roles of DUBs in key cancer-related pathways. We also discuss the clinical applications of promising DUB inhibitors that may contribute to the development of DUBs as key therapeutic targets in the future.

scholarly journals Protein Stability of Pyruvate Kinase Isozyme M2 Is Mediated by HAUSP

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1548 ◽  
Author(s):  
Hae-Seul Choi ◽  
Chang-Zhu Pei ◽  
Jun-Hyeok Park ◽  
Soo-Yeon Kim ◽  
Seung-Yeon Song ◽  
...  
Keyword(s):  
Pyruvate Kinase ◽  
Tumor Development ◽  
Direct Interaction ◽  
Ubiquitin Proteasome System ◽  
Binding Motif ◽  
Deubiquitinating Enzymes ◽  
Flight Mass Spectrometry ◽  
Specific Protease ◽  
Ubiquitin Proteasome ◽  
Mutant Forms

The ubiquitin–proteasome system (UPS) is responsible for proteasomal degradation, regulating the half-life of the protein. Deubiquitinating enzymes (DUBs) are components of the UPS and inhibit degradation by removing ubiquitins from protein substrates. Herpesvirus-associated ubiquitin-specific protease (HAUSP) is one such deubiquitinating enzyme and has been closely associated with tumor development. In a previous study, we isolated putative HAUSP binding substrates by two-dimensional electrophoresis (2-DE) and identified them by matrix-assisted laser desorption-ionization time-of-flight mass spectrometry (MALDI-TOF/MS) analysis. The analysis showed that pyruvate kinase isoenzyme M2 (PKM2) was likely to be one of the substrates for HAUSP. Further study revealed that PKM2 binds to HAUSP, confirming the interaction between these proteins, and that PKM2 possesses the putative HAUSP binding motif, E or P/AXXS. Therefore, we generated mutant forms of PKM2 S57A, S97A, and S346A, and found that S57A had less binding affinity. In a previous study, we demonstrated that PKM2 is regulated by the UPS, and that HAUSP- as a DUB-acted on PKM2, thus siRNA for HAUSP increases PKM2 ubiquitination. Our present study newly highlights the direct interaction between HAUSP and PKM2.

scholarly journals Fungal Secondary Metabolites as Inhibitors of the Ubiquitin–Proteasome System

2021 ◽  
Vol 22 (24) ◽  
pp. 13309
Author(s):  
Magdalena Staszczak
Keyword(s):  
Secondary Metabolites ◽  
Control Function ◽  
Cell Cycle Control ◽  
Regulation Of Gene Expression ◽  
Proteasome Inhibitors ◽  
Ubiquitin Proteasome System ◽  
Regulatory Function ◽  
Deubiquitinating Enzymes ◽  
Ubiquitin Proteasome ◽  
Fungal Secondary Metabolites

The ubiquitin–proteasome system (UPS) is the major non-lysosomal pathway responsible for regulated degradation of intracellular proteins in eukaryotes. As the principal proteolytic pathway in the cytosol and the nucleus, the UPS serves two main functions: the quality control function (i.e., removal of damaged, misfolded, and functionally incompetent proteins) and a major regulatory function (i.e., targeted degradation of a variety of short-lived regulatory proteins involved in cell cycle control, signal transduction cascades, and regulation of gene expression and metabolic pathways). Aberrations in the UPS are implicated in numerous human pathologies such as cancer, neurodegenerative disorders, autoimmunity, inflammation, or infectious diseases. Therefore, the UPS has become an attractive target for drug discovery and development. For the past two decades, much research has been focused on identifying and developing compounds that target specific components of the UPS. Considerable effort has been devoted to the development of both second-generation proteasome inhibitors and inhibitors of ubiquitinating/deubiquitinating enzymes. With the feature of unique structure and bioactivity, secondary metabolites (natural products) serve as the lead compounds in the development of new therapeutic drugs. This review, for the first time, summarizes fungal secondary metabolites found to act as inhibitors of the UPS components.

scholarly journals The Ubiquitin Proteasome System in Periodontal Disease: A Comprehensive Review

2020 ◽  
Vol 1 ◽  
Author(s):  
Vanessa Machado ◽  
Rui Carvalho ◽  
José João Mendes ◽  
João Botelho
Keyword(s):  
Periodontal Disease ◽  
Periodontal Diseases ◽  
Ubiquitin Proteasome System ◽  
Substrate Protein ◽  
Disease Therapy ◽  
Intracellular Proteins ◽  
Ubiquitin Proteasome ◽  
Ubiquitin Conjugation ◽  
Turn Over

The turnover of intracellular proteins is a highly selective and regulated process. This process is responsible for avoiding injury and irreparable breakdown of cellular constituents. Its impairment disrupts cellular stability, integrity, and homeostasis. The ubiquitin-proteasome system (UPS) is responsible for this programmed degradation of most intracellular proteins. This process involves a cascade of enzymes that involves the ubiquitin conjugation to a target substrate protein, its recognition and degradation by the proteasome. The turn-over of intracellular proteins is a non-stop ubiquitous process that regulates a series of mechanisms, for instance transcription, translation, endocytosis. In addition, proteasome act by releasing peptides that may serve to other purposes, such as antigen presentation in immune actions and enzymatic flagging toward biosynthesis and gluconeogenesis. The role of the UPS impairment in periodontal diseases is gaining growing. This acquaintance might contribute to the development of novel therapeutic applications. Thus, this review focuses on the latest progresses on the role of the UPS and its signaling pathways in Periodontal Medicine. Furthermore, we discuss the potential of UPS-based drugs development to be used in periodontal disease therapy.

Sign in / Sign up

Export Citation Format

Share Document