Targeting the ubiquitin-proteasome system for cancer therapy - PubMed (original) (raw)

Review

Targeting the ubiquitin-proteasome system for cancer therapy

Yili Yang et al. Cancer Sci. 2009 Jan.

Abstract

The ubiquitin-proteasome system plays a critical role in controlling the level, activity and location of various cellular proteins. Significant progress has been made in investigating the molecular mechanisms of ubiquitination, particularly in understanding the structure of the ubiquitination machinery and identifying ubiquitin protein ligases, the primary specificity-determining enzymes. Therefore, it is now possible to target specific molecules involved in ubiquitination and proteasomal degradation to regulate many cellular processes such as signal transduction, proliferation and apoptosis. In particular, alterations in ubiquitination are observed in most, if not all, cancer cells. This is manifested by destabilization of tumor suppressors, such as p53, and overexpression of oncogenes such as c-Myc and c-Jun. In addition to the development and clinical validation of proteasome inhibitor, bortezomib, in myeloma therapy, recent studies have demonstrated that it is possible to develop inhibitors for specific ubiquitination and deubiquitination enzymes. With the help of structural studies, rational design and chemical synthesis, it is conceivable that we will be able to use 'druggable' inhibitors of the ubiquitin system to evaluate their effects in animal tumor models in the not-so-distant future.

PubMed Disclaimer

Figures

Figure 1

Figure 1

The ubiquitination cascade. Ubiquitin (Ub) is activated by E1 and conjugated to the active Cys of E1 through thioester bond. Activated Ub is then transferred to E2 that can bind with E3. An RING‐containing E3 facilitates the transfer of activated Ub to substrate from E2 directly, whereas a HECT domain E3 forms thioester bond with activated Ub and then transfer it to substrate. Monoubiquitination of target protein enable its recognition by many Ub‐recognizing domains in cells, leading to alteration of protein activity and location in cells. Formation of K48‐linked polyubiquitin chains on substrate proteins result in their degradation in proteasomes. Formation of K63‐linked polyubiquitin chains are involved in cellular processes such as signal transduction and DNA repair. AMP, adenosine triphosphate; ATP, adenosine monophosphate.

Figure 2

Figure 2

Inhibitors that block the Hdm2‐mediated ubiquitination and proteasomal degradation of p53.

Similar articles

Cited by

References

    1. Hershko A. Ubiquitin. roles in protein modification and breakdown. Cell 1983; 34: 11–12. - PubMed
    1. Kuo ML, Den Besten W, Bertwistle D, Roussel MF, Sherr CJ. N‐terminal polyubiquitination and degradation of the Arf tumor suppressor. Genes Dev 2004; 18: 1862–74. - PMC - PubMed
    1. Cadwell K, Coscoy L. Ubiquitination on nonlysine residues by a viral E3 ubiquitin ligase. Science 2005; 309: 127–30. - PubMed
    1. Hoppe T. Multiubiquitylation by E4 enzymes: ‘one size’ doesn't fit all. Trends Biochem Sci 2005; 30: 183–7. - PubMed
    1. Hoeller D, Hecker CM, Wagner S, Rogov V, Dotsch V, Dikic I. E3‐independent monoubiquitination of ubiquitin‐binding proteins. Mol Cell 2007; 26: 891–8. - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources