The intriguing role of USP30 inhibitors as deubiquitinating enzymes from the patent literature since 2013

2021 ◽  
Author(s):  
Sofia Ferrer Cabrera ◽  
Michael E. Muratore ◽  
Peter Buijnsters
Keyword(s):  
Deubiquitinating Enzymes ◽  
Patent Literature

PI3K/ Akt/ mTOR Pathway as a Therapeutic Target for Colorectal Cancer: A Review of Preclinical and Clinical Evidence

2019 ◽  
Vol 20 (12) ◽  
pp. 1217-1226 ◽  
Author(s):  
Arunaksharan Narayanankutty
Keyword(s):  
Colorectal Cancer ◽  
Drug Resistance ◽  
Therapeutic Target ◽  
Clinical Evidence ◽  
Mtor Pathway ◽  
Colorectal Cancers ◽  
Patent Literature ◽  
Mtor Signalling ◽  
Natural And Synthetic

Background: Phosphoinositide 3-kinase (PI3Ks) is a member of intracellular lipid kinases and involved in the regulation of cellular proliferation, differentiation and survival. Overexpression of the PI3K/Akt/mTOR signalling has been reported in various forms of cancers, especially in colorectal cancers (CRC). Due to their significant roles in the initiation and progression events of colorectal cancer, they are recognized as a striking therapeutic target. Objective: The present review is aimed to provide a detailed outline on the role of PI3K/Akt/mTOR pathway in the initiation and progression events of colorectal cancers as well as its function in drug resistance. Further, the role of PI3K/Akt/mTOR inhibitors alone and in combination with other chemotherapeutic drugs, in alleviating colorectal cancer is also discussed. The review contains preclinical and clinical evidence as well as patent literature of the pathway inhibitors which are natural and synthetic in origin. Methods: The data were obtained from PubMed/Medline databases, Scopus and Google patent literature. Results: PI3K/Akt/mTOR signalling is an important event in colorectal carcinogenesis. In addition, it plays significant roles in acquiring drug resistance as well as metastatic initiation events of CRCs. Several small molecules of natural and synthetic origin have been found to be potent inhibitors of CRCs by effectively downregulating the pathway. Data from various clinical studies also support these pathway inhibitors and several among them are patented. Conclusion: Inhibitors of the PI3K/mTOR pathway have been successful for the treatment of primary and metastatic colorectal cancers, rendering the pathway as a promising clinical cancer therapeutic target.

scholarly journals Role of Virally-Encoded Deubiquitinating Enzymes in Regulation of the Virus Life Cycle

2021 ◽  
Vol 22 (9) ◽  
pp. 4438
Author(s):  
Jessica Proulx ◽  
Kathleen Borgmann ◽  
In-Woo Park
Keyword(s):  
Immune Response ◽  
Life Cycle ◽  
Deubiquitinating Enzyme ◽  
Deubiquitinating Enzymes ◽  
Antiviral Immune Response ◽  
Cellular Processes ◽  
Virus Life Cycle ◽  
Infected Cells ◽  
Dependent Processes

The ubiquitin (Ub) proteasome system (UPS) plays a pivotal role in regulation of numerous cellular processes, including innate and adaptive immune responses that are essential for restriction of the virus life cycle in the infected cells. Deubiquitination by the deubiquitinating enzyme, deubiquitinase (DUB), is a reversible molecular process to remove Ub or Ub chains from the target proteins. Deubiquitination is an integral strategy within the UPS in regulating survival and proliferation of the infecting virus and the virus-invaded cells. Many viruses in the infected cells are reported to encode viral DUB, and these vial DUBs actively disrupt cellular Ub-dependent processes to suppress host antiviral immune response, enhancing virus replication and thus proliferation. This review surveys the types of DUBs encoded by different viruses and their molecular processes for how the infecting viruses take advantage of the DUB system to evade the host immune response and expedite their replication.

scholarly journals DUBs and cancer: The role of deubiquitinating enzymes as oncogenes, non-oncogenes and tumor suppressors

Cell Cycle ◽  
2009 ◽  
Vol 8 (11) ◽  
pp. 1688-1697 ◽  
Author(s):  
Sajjad Hussain ◽  
Ying Zhang ◽  
Paul Galardy
Keyword(s):  
Tumor Suppressors ◽  
Deubiquitinating Enzymes

scholarly journals Essential Role of Ubiquitin-Specific Protease 8 for Receptor Tyrosine Kinase Stability and Endocytic Trafficking In Vivo

2007 ◽  
Vol 27 (13) ◽  
pp. 5029-5039 ◽  
Author(s):  
Sandra Niendorf ◽  
Alexander Oksche ◽  
Agnes Kisser ◽  
Jürgen Löhler ◽  
Marco Prinz ◽  
...  
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinases ◽  
Growth Regulation ◽  
Growth Factor Receptor ◽  
Deubiquitinating Enzymes ◽  
Cellular Functions ◽  
Early Endosomes ◽  
Immortalized Cells

ABSTRACT Posttranslational modification by ubiquitin controls multiple cellular functions and is counteracted by the activities of deubiquitinating enzymes. UBPy (USP8) is a growth-regulated ubiquitin isopeptidase that interacts with the HRS-STAM complex. Using Cre-loxP-mediated gene targeting in mice, we show that lack of UBPy results in embryonic lethality, whereas its conditional inactivation in adults causes fatal liver failure. The defect is accompanied by a strong reduction or absence of several growth factor receptor tyrosine kinases (RTKs), like epidermal growth factor receptor, hepatocyte growth factor receptor (c-met), and ERBB3. UBPy-deficient cells exhibit aberrantly enlarged early endosomes colocalizing with enhanced ubiquitination and have reduced levels of HRS and STAM2. Congruently immortalized cells gradually stop proliferation upon induced deletion of UBPy. These results unveil a central and nonredundant role of UBPy in growth regulation, endosomal sorting, and the control of RTKs in vivo.

scholarly journals Active site alanine substitutions can convert deubiquitinating enzymes into avid ubiquitin-binding domains

2017 ◽  
Author(s):  
Marie Morrow ◽  
Michael Morgan ◽  
Marcello Clerici ◽  
Katerina Growkova ◽  
Ming Yan ◽  
...  
Keyword(s):  
Active Site ◽  
Tight Binding ◽  
Dominant Negative ◽  
Structural Basis ◽  
Deubiquitinating Enzymes ◽  
Active Site Cysteine ◽  
Binding Domains ◽  
Common Strategy ◽  
Catalytic Cysteine

ABSTRACTA common strategy for studying the biological role of deubiquitinating enzymes (DUBs) in different pathways is to study the effects of replacing the wild type DUB with a catalytically inactive mutant in cells. We report here that a commonly studied DUB mutation, in which the catalytic cysteine is replaced with alanine, can dramatically increase the affinity of some DUBs for ubiquitin. Overexpression of these tight-binding mutants thus has the potential to sequester cellular pools of monoubiquitin and ubiquitin chains. As a result, cells expressing these mutants may display unpredictable dominant negative physiological effects that are not related to loss of DUB activity. The structure of the SAGA DUB module bound to free ubiquitin reveals the structural basis for the 30-fold higher affinity of Ubp8C146A for ubiquitin. We show that an alternative option, substituting the active site cysteine with arginine, can inactivate DUBs while also decreasing the affinity for ubiquitin.

scholarly journals The Role of Deubiquitinating Enzymes in Hematopoiesis and Hematological Malignancies

2020 ◽  
Author(s):  
Neha Sarodaya ◽  
Janardhan Karapurkar ◽  
Kye-Seong Kim ◽  
Seok-Ho Hong ◽  
Suresh Ramakrishna
Keyword(s):  
Drug Targets ◽  
Molecular Mechanisms ◽  
Human Life ◽  
Therapeutic Drug ◽  
Cellular Interactions ◽  
Deubiquitinating Enzymes ◽  
Hematopoietic Stem ◽  
Hematological Disorders ◽  
Additional Information

Hematopoietic stem cells (HSCs) are responsible for the production of blood cells throughout the human life span. Single HSCs can give rise to at least eight distinct blood cell lineages. Together, hematopoiesis, erythropoiesis and angiogenesis coordinate several biological processes, such as cellular interactions in development and proliferation, guided migration, lineage programming and reprogramming by transcription factors. Any dysregulation of these processes may result in hematological disorders and/or malignancies. Several studies of the molecular mechanisms governing HSC maintenance have demonstrated that protein regulation by the ubiquitin proteasomal pathway is crucial for normal HSC function. Recent studies have shown that the reversal of ubiquitination by deubiquitinating enzymes (DUBs) plays an equally important role in hematopoiesis; however, there is only limited additional information regarding the biological function of DUBs. In this review, we focus on recent discoveries that have led to a better understanding of the physiological roles of DUBs in hematopoiesis, erythropoiesis and angiogenesis. In addition, we discuss the DUBs associated with common hematological disorders and malignancies, which may potentially be therapeutic drug targets.

scholarly journals USP48 Governs Cell Cycle Progression by Regulating the Protein Level of Aurora B

2021 ◽  
Vol 22 (16) ◽  
pp. 8508
Author(s):  
Ainsley Mike Antao ◽  
Kamini Kaushal ◽  
Soumyadip Das ◽  
Vijai Singh ◽  
Bharathi Suresh ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Aurora B ◽  
Deubiquitinating Enzymes ◽  
Cycle Progression ◽  
Protein Levels ◽  
Steady State Levels ◽  
Cycle Regulation ◽  
Normal Cell Cycle

Deubiquitinating enzymes play key roles in the precise modulation of Aurora B—an essential cell cycle regulator. The expression of Aurora B increases before the onset of mitosis and decreases during mitotic exit; an imbalance in these levels has a severe impact on the fate of the cell cycle. Dysregulation of Aurora B can lead to aberrant chromosomal segregation and accumulation of errors during mitosis, eventually resulting in cytokinesis failure. Thus, it is essential to identify the precise regulatory mechanisms that modulate Aurora B levels during the cell division cycle. Using a deubiquitinase knockout strategy, we identified USP48 as an important candidate that can regulate Aurora B protein levels during the normal cell cycle. Here, we report that USP48 interacts with and stabilizes the Aurora B protein. Furthermore, we showed that the deubiquitinating activity of USP48 helps to maintain the steady-state levels of Aurora B protein by regulating its half-life. Finally, USP48 knockout resulted in delayed progression of cell cycle due to accumulation of mitotic defects and ultimately cytokinesis failure, suggesting the role of USP48 in cell cycle regulation.

scholarly journals The Role of Deubiquitinating Enzymes in Hematopoiesis and Hematological Malignancies

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1103 ◽  
Author(s):  
Neha Sarodaya ◽  
Janardhan Karapurkar ◽  
Kye-Seong Kim ◽  
Seok-Ho Hong ◽  
Suresh Ramakrishna
Keyword(s):  
Drug Targets ◽  
Molecular Mechanisms ◽  
Therapeutic Drug ◽  
Cellular Interactions ◽  
Deubiquitinating Enzymes ◽  
Hematopoietic Stem ◽  
Hematological Disorders ◽  
Cell Lineages ◽  
Human Lifespan

Hematopoietic stem cells (HSCs) are responsible for the production of blood cells throughout the human lifespan. Single HSCs can give rise to at least eight distinct blood-cell lineages. Together, hematopoiesis, erythropoiesis, and angiogenesis coordinate several biological processes, i.e., cellular interactions during development and proliferation, guided migration, lineage programming, and reprogramming by transcription factors. Any dysregulation of these processes can result in hematological disorders and/or malignancies. Several studies of the molecular mechanisms governing HSC maintenance have demonstrated that protein regulation by the ubiquitin proteasomal pathway is crucial for normal HSC function. Recent studies have shown that reversal of ubiquitination by deubiquitinating enzymes (DUBs) plays an equally important role in hematopoiesis; however, information regarding the biological function of DUBs is limited. In this review, we focus on recent discoveries about the physiological roles of DUBs in hematopoiesis, erythropoiesis, and angiogenesis and discuss the DUBs associated with common hematological disorders and malignancies, which are potential therapeutic drug targets.

The role of deubiquitinating enzymes in cancer drug resistance

2020 ◽  
Vol 85 (4) ◽  
pp. 627-639
Author(s):  
Parthasaradhireddy Tanguturi ◽  
Kye-Seong Kim ◽  
Suresh Ramakrishna
Keyword(s):  
Drug Resistance ◽  
Cancer Drug ◽  
Deubiquitinating Enzymes ◽  
Cancer Drug Resistance

Development of Ubiquitin Tools for Studies of Complex Ubiquitin Processing Protein Machines

2020 ◽  
Vol 23 (23) ◽  
pp. 2614-2625
Author(s):  
Xin Sui ◽  
Yi-Ming Li
Keyword(s):  
Protein Localization ◽  
The Other ◽  
Related Protein ◽  
Deubiquitinating Enzymes ◽  
Post Translational Modifications ◽  
Physiological Processes ◽  
Complex Protein ◽  
Recombinant Technology ◽  
Functional Mechanisms

: Ubiquitination is one of the most extensive post-translational modifications in eukaryotes and is involved in various physiological processes such as protein degradation, autophagy, protein interaction, and protein localization. The ubiquitin (Ub)-related protein machines include Ub-activating enzymes (E1s), Ub-conjugating enzymes (E2s), Ub ligases (E3s), deubiquitinating enzymes (DUBs), p97, and the proteasomes. In recent years, the role of DUBs has been extensively studied and relatively well understood. On the other hand, the functional mechanisms of the other more complex ubiquitin-processing protein machines (e.g., E3, p97, and proteasomes) are still to be sufficiently well explored due to their intricate nature. One of the hurdles facing the studies of these complex protein machines is the challenge of developing tailor-designed structurally defined model substrates, which unfortunately cannot be directly obtained using recombinant technology. Consequently, the acquisition and synthesis of the ubiquitin tool molecules are essential for the elucidation of the functions and structures of the complex ubiquitin-processing protein machines. This paper aims to highlight recent studies on these protein machines based on the synthetic ubiquitin tool molecules.

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