Abstract
Intracellular protein degradation is a tightly regulated process that in many cases is controlled by protein ubiquitylation. The ubiquitin pathway is a major route by which cells not only remove normal proteins at the appropriate time but also abnormally folded normal or mutant, cytoplasmic and membrane, proteins. This has led to a major impetus to identify constituents of the pathway. The key components that regulate substrate ubiquitylation are the ubiquitin-protein ligases. Ligases come in many forms, from single proteins to very large multiprotein complexes. Specificity of targeting can be modulated by the requirement for post-translational modifications such as phosphorylation, hydroxylation or oxidation of the substrate and, in some cases, the ligase itself. The requirement for substrate modification prior to ubiquitylation allows the same ligase to target different substrates within the same cell at different times. Abnormal intracellular protein processing is a common feature of many human diseases including neurodegenerative diseases and cancer. It may not represent the causative factor that initiates the disease process but may be a downstream regulator of the toxic effect. These abnormalities often arise from the loss of a key protein-protein interaction. As a consequence, mutated proteins can have very different half-lives from their normal counterparts. This can affect the levels of their activity and / or lead to the formation of protein aggregates (inclusion bodies / aggresomes). In this review, we aim to highlight examples of diseases where abnormal protein ubiquitylation is proposed to be a key regulator of the disease process. The recent success of the proteasome inhibitor Bortezomib (PS-341) for treatment of relapsed, refractory myeloma suggests that the modulation of individual ubiquitin-protein ligase activities with synthetic agents may represent a novel approach that has enormous potential for the treatment of a wide range of diseases.
Keywords: ubiquitin, ubiquitin-protein ligases, ubiquitylation, protein aggregates
Current Protein & Peptide Science
Title: Ubiquitin-Protein Ligases - Novel Therapeutic Targets?
Volume: 5 Issue: 3
Author(s): Philip A. Robinson and Helen C. Ardley
Affiliation:
Keywords: ubiquitin, ubiquitin-protein ligases, ubiquitylation, protein aggregates
Abstract: Intracellular protein degradation is a tightly regulated process that in many cases is controlled by protein ubiquitylation. The ubiquitin pathway is a major route by which cells not only remove normal proteins at the appropriate time but also abnormally folded normal or mutant, cytoplasmic and membrane, proteins. This has led to a major impetus to identify constituents of the pathway. The key components that regulate substrate ubiquitylation are the ubiquitin-protein ligases. Ligases come in many forms, from single proteins to very large multiprotein complexes. Specificity of targeting can be modulated by the requirement for post-translational modifications such as phosphorylation, hydroxylation or oxidation of the substrate and, in some cases, the ligase itself. The requirement for substrate modification prior to ubiquitylation allows the same ligase to target different substrates within the same cell at different times. Abnormal intracellular protein processing is a common feature of many human diseases including neurodegenerative diseases and cancer. It may not represent the causative factor that initiates the disease process but may be a downstream regulator of the toxic effect. These abnormalities often arise from the loss of a key protein-protein interaction. As a consequence, mutated proteins can have very different half-lives from their normal counterparts. This can affect the levels of their activity and / or lead to the formation of protein aggregates (inclusion bodies / aggresomes). In this review, we aim to highlight examples of diseases where abnormal protein ubiquitylation is proposed to be a key regulator of the disease process. The recent success of the proteasome inhibitor Bortezomib (PS-341) for treatment of relapsed, refractory myeloma suggests that the modulation of individual ubiquitin-protein ligase activities with synthetic agents may represent a novel approach that has enormous potential for the treatment of a wide range of diseases.
Export Options
About this article
Cite this article as:
Robinson A. Philip and Ardley C. Helen, Ubiquitin-Protein Ligases - Novel Therapeutic Targets?, Current Protein & Peptide Science 2004; 5 (3) . https://dx.doi.org/10.2174/1389203043379800
DOI https://dx.doi.org/10.2174/1389203043379800 |
Print ISSN 1389-2037 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5550 |
![](/images/wayfinder.jpg)
- Author Guidelines
- Bentham Author Support Services (BASS)
- 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
Related Articles
-
Mechanisms of ERK1/2 Regulation by Seven-Transmembrane-Domain Receptors
Current Pharmaceutical Design Meet Our Editorial Board Member
Recent Patents on Inflammation & Allergy Drug Discovery Gene Therapy Using an Adenovirus Vector for Apoptosis-Related Genes is a Highly Effective Therapeutic Modality for Killing Glioma Cells
Current Gene Therapy Targeting the Endocannabinod System to Limit Myocardial and Cerebral Ischemic and Reperfusion Injury
Current Pharmaceutical Biotechnology Anlotinib Inhibits Cell Proliferation, Migration and Invasion via Suppression of c-Met Pathway and Activation of ERK1/2 Pathway in H446 Cells
Anti-Cancer Agents in Medicinal Chemistry Neuro-Transmitters in the Central Nervous System & their Implication in Learning and Memory Processes
Current Medicinal Chemistry Aflibercept (VEGF-TRAP): The Next Anti-VEGF Drug
Inflammation & Allergy - Drug Targets (Discontinued) AKT-pathway Inhibition in Chronic Lymphocytic Leukemia Reveals Response Relationships Defined by TCL1
Current Cancer Drug Targets Progress in Developing Amphiphilic Cyclodextrin-Based Nanodevices for Drug Delivery
Current Topics in Medicinal Chemistry Applications of Molecular Imaging in Cancer Gene Therapy
Current Gene Therapy Blockade of Furin Activity and Furin-Induced Tumor Cells Malignant Phenotypes By The Chemically Synthesized Human Furin Prodomain
Current Medicinal Chemistry Regulation of Mitochondrial Function and its Impact in Metabolic Stress
Current Medicinal Chemistry Endocannabinoids and Their Receptors: Physiology, Pathology and Pharmacology
Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Discontinued) Expression and Function of Angiomodulating Cytokines in Rheumatoid Arthritis and Experimental Arthritis: Important Therapeutic Targets
Current Immunology Reviews (Discontinued) Targeting the Akt-pathway to Improve Radiosensitivity in Glioblastoma
Current Pharmaceutical Design Current Phthalocyanines Delivery Systems in Photodynamic Therapy: An Updated Review
Current Medicinal Chemistry Angiotensin Peptides and Lung Cancer
Current Cancer Drug Targets Effect of O6-Substituted Guanine Analogs on O6-methylguanine DNA-methyltransferase Expression and Glioblastoma Cells Viability
Medicinal Chemistry Antisense Oligonucleotides in the Treatment of Cerebral Gliomas. Review of Concerning Patents
Recent Patents on CNS Drug Discovery (Discontinued) Cell-Penetrating Peptide-Mediated Therapeutic Molecule Delivery into the Central Nervous System
Current Neuropharmacology