Abstract
The proteasomal pathway of protein degradation involves two discrete steps: ubiquitination and degradation. Blocking protein degradation by inhibiting the proteasome has well described biologic effects and proteasome inhibitors are approved for the treatment of multiple myeloma and mantle cell lymphoma. In contrast, the biological effects and potential therapeutic utility of inhibiting the ubiquitination cascade and the initiating enzyme UBA1 are less well understood. UBA1 is the initial enzyme in the ubiquitination cascade and initiates the transfer of ubiquitin molecules to target proteins where they are degraded by the proteasome. Here, we review the biological effects of UBA1 inhibition and discuss UBA1 inhibitors as potential anti-cancer agents. Similar to proteasome inhibition, blocking UBA1 elicits an unfolded protein response and induces cell death in malignant cells over normal cells. Chemical UBA1 inhibitors have been developed that target different regions of the enzyme and inhibit its function through different mechanisms. These molecules are useful tools to understand the biology of UBA1 and highlight the potential of inhibiting this target for the treatment of malignancy.
Keywords: Ubiquitin, proteasome, UBA1.
Current Pharmaceutical Design
Title:Targeting the Ubiquitin E1 as a Novel Anti-Cancer Strategy
Volume: 19 Issue: 18
Author(s): Wei Xu, Julie L. Lukkarila, Sara R. da Silva, Stacey-Lynn Paiva, Patrick T. Gunning and Aaron D. Schimmer
Affiliation:
Keywords: Ubiquitin, proteasome, UBA1.
Abstract: The proteasomal pathway of protein degradation involves two discrete steps: ubiquitination and degradation. Blocking protein degradation by inhibiting the proteasome has well described biologic effects and proteasome inhibitors are approved for the treatment of multiple myeloma and mantle cell lymphoma. In contrast, the biological effects and potential therapeutic utility of inhibiting the ubiquitination cascade and the initiating enzyme UBA1 are less well understood. UBA1 is the initial enzyme in the ubiquitination cascade and initiates the transfer of ubiquitin molecules to target proteins where they are degraded by the proteasome. Here, we review the biological effects of UBA1 inhibition and discuss UBA1 inhibitors as potential anti-cancer agents. Similar to proteasome inhibition, blocking UBA1 elicits an unfolded protein response and induces cell death in malignant cells over normal cells. Chemical UBA1 inhibitors have been developed that target different regions of the enzyme and inhibit its function through different mechanisms. These molecules are useful tools to understand the biology of UBA1 and highlight the potential of inhibiting this target for the treatment of malignancy.
Export Options
About this article
Cite this article as:
Xu Wei, Lukkarila Julie L., da Silva Sara R., Paiva Stacey-Lynn, Gunning Patrick T. and Schimmer Aaron D., Targeting the Ubiquitin E1 as a Novel Anti-Cancer Strategy, Current Pharmaceutical Design 2013; 19 (18) . https://dx.doi.org/10.2174/1381612811319180004
DOI https://dx.doi.org/10.2174/1381612811319180004 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
Call for Papers in Thematic Issues
"Tuberculosis Prevention, Diagnosis and Drug Discovery"
The Nobel Prize-winning discoveries of Mycobacterium tuberculosis and streptomycin have enabled an appropriate diagnosis and an effective treatment of tuberculosis (TB). Since then, many newer diagnosis methods and drugs have been saving millions of lives. Despite advances in the past, TB is still a leading cause of infectious disease mortality ...read more
Current Pharmaceutical challenges in the treatment and diagnosis of neurological dysfunctions
Neurological dysfunctions (MND, ALS, MS, PD, AD, HD, ALS, Autism, OCD etc..) present significant challenges in both diagnosis and treatment, often necessitating innovative approaches and therapeutic interventions. This thematic issue aims to explore the current pharmaceutical landscape surrounding neurological disorders, shedding light on the challenges faced by researchers, clinicians, and ...read more
Emerging and re-emerging diseases
Faced with a possible endemic situation of COVID-19, the world has experienced two important phenomena, the emergence of new infectious diseases and/or the resurgence of previously eradicated infectious diseases. Furthermore, the geographic distribution of such diseases has also undergone changes. This context, in turn, may have a strong relationship with ...read more
Melanoma and Non-Melanoma Skin Cancer Treatment: Standard of Care and Recent Advances
In this thematic issue, we aim to provide a standard of care of the diagnosis and treatment of melanoma and non-melanoma skin cancer. The editor will invite authors from different countries who will write review articles of melanoma and non-melanoma skin cancers. The Diagnosis, Staging, Surgical Treatment, Non-Surgical Treatment all ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Aberrant Expression of MicroRNAs in B-cell Lymphomas
MicroRNA Brief Academic Review and Clinical Practice Guidelines for Pediatric Atopic Dermatitis
Current Pediatric Reviews Epigenetic and miRNAs Dysregulation in Prostate Cancer: The role of Nutraceuticals
Anti-Cancer Agents in Medicinal Chemistry From Bortezomib to other Inhibitors of the Proteasome and Beyond
Current Pharmaceutical Design Cell Death in Mammalian Development
Current Pharmaceutical Design Differentiation of Glioblastoma and Lymphoma Using Feature Extraction and Support Vector Machine
CNS & Neurological Disorders - Drug Targets Exploiting EPR in Polymer Drug Conjugate Delivery for Tumor Targeting
Current Pharmaceutical Design Apoptosis Induction by Erucylphosphohomocholine via the 18 kDa Mitochondrial Translocator Protein: Implications for Cancer Treatment
Anti-Cancer Agents in Medicinal Chemistry PI3K/AKT/mTOR Inhibitors In Ovarian Cancer
Current Medicinal Chemistry subject Index To Volume 2
Current Pharmaceutical Biotechnology Proteomics Annotation of Lipid Rafts Modified by Virus Infection
Combinatorial Chemistry & High Throughput Screening Editorial (Thematic Issue: Immunophilins, Protein Chemistry and Cell Biology of a Promising New Class of Drug Targets – Part II)
Current Molecular Pharmacology Small Molecule Inhibitors of Phosphoinositide 3-Kinase (PI3K) δ and γ
Current Topics in Medicinal Chemistry Cells Under Pressure – Treatment of Eukaryotic Cells with High Hydrostatic Pressure, from Physiologic Aspects to Pressure Induced Cell Death
Current Medicinal Chemistry Feud or Friend? The Role of the miR-17-92 Cluster in Tumorigenesis
Current Genomics Ribonucleases and ImmunoRNases as Anticancer Drugs
Current Pharmaceutical Design Interaction of Human Brain Acetylcholinesterase with Cyclophosphamide: A Molecular Modeling and Docking Study
CNS & Neurological Disorders - Drug Targets The Akt-mTOR Pathway in Down’s Syndrome: The Potential Use of Rapamycin/Rapalogs for Treating Cognitive Deficits
CNS & Neurological Disorders - Drug Targets Toll-Like Receptors and Human Disease: Lessons from Single Nucleotide Polymorphisms
Current Genomics Upregulation of Focal Adhesion Kinase by 14-3-3ε via NFκB Activation in Hepatocellular Carcinoma
Anti-Cancer Agents in Medicinal Chemistry