Elsevier

Molecular Genetics and Metabolism

Volume 77, Issues 1–2, September–October 2002, Pages 44-56
Molecular Genetics and Metabolism

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Ubiquitin-dependent proteolysis: its role in human diseases and the design of therapeutic strategies

https://doi.org/10.1016/S1096-7192(02)00146-4Get rights and content

Abstract

Protein degradation is one of the tactics employed by the cell for irreversibly inactivating proteins. In eukaryotes, ATP-dependent protein degradation in the cytoplasm and nucleus is carried out by the 26S proteasome. Most proteins are targeted to the 26S proteasome by covalent attachment of a multi-ubiquitin chain. A key component of the enzyme cascade that results in attachment of the multi-ubiquitin chain to the target or labile protein is the ubiquitin ligase that controls the specificity of the ubiquitination reaction. Defects in ubiquitin-dependent proteolysis have been shown to result in a variety of human diseases, including cancer, neurodegenerative diseases, and metabolic disorders. This review focuses on the role of ubiquitin-dependent degradation in human disease and potential clinical applications that are being developed to exploit the cells natural proteolytic machinery to treat diseases.

Introduction

Ubiquitin (Ub)-dependent proteolysis of key regulatory proteins impacts various cellular processes such as cell cycle progression, transcription, antigen presentation, receptor endocytosis, fate determination, and signal transduction [1], [2]. With so many cellular pathways affected, it is therefore not surprising that derangements in the Ub-proteolytic pathway contribute to the etiology of several diseases. In this review, we will summarize our current understanding of how Ub-dependent degradation takes place in the cell and the various steps at which an impairment of the normal pathway contributes to the diseased state. We will conclude by summarizing the different ways we, as well as others, are utilizing the cellular degradation machinery to develop therapeutic strategies to treat human diseases.

Section snippets

The Ubiquitin system

Ubiquitin is one of the most conserved proteins in eukaryotes. It is a small 76-amino acid protein that is conjugated to other proteins through an energy-dependent enzymatic pathway [1], [3]. Conjugation is initiated by the activation of Ub by the Ub-activating enzyme, E1, which forms a high-energy Ub-thiol ester bond in the presence of ATP (Fig. 1). It then transfers the activated Ub to a Ub-conjugating enzyme, E2, forming an E2-thiol ester bond. Finally, ubiquitin is transferred to a target

Cervical cancer

Among the best-characterized associations between cancer and the ubiquitin ligase pathway is that of cancer of the uterine cervix. This is the third most common cancer diagnosed in women. While the precise cause of cervical cancer remains uncertain, the disease is strongly associated with infections by the oncogenic forms of HPV, types 16 and 18. The E6 and E7 proteins of these high risk strains are often detected in cervical cancers [44]. In these same carcinomas, the levels of tumor

Potential therapeutic strategies

Given the fact that all mammalian cells have ubiquitin ligases and proteasomes, selectively targeting proteins for ubiquitination and degradation is a potential avenue for drug development. Moreover, since there is recent information about the crystal structure of ubiquitin ligases and their substrates, one could imagine using low molecular weight compounds to stabilize or degrade proteins to treat a variety of diseases. Several approaches have been considered, including gene therapy to

Acknowledgements

I thank Ray Deshaies for his support and helpful comments, Rati Verma for helpful suggestions and critical reading of the manuscript, Craig Crews for providing the Protacs, and Ning Zheng for providing purified Cbl, ubch4, and GST-E1 for ubiquitination assays. This work was supported by CaPCURE and the UC BioSTAR Project (biostar 01-10232). I also thank Frank Mercurio and Celgene, Signal Research Division for supporting this work and providing reagents. K.M.S. is a Scholar of the Leukemia and

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