Ubiquitin becomes ubiquitous in cancer

Abstract

By virtue of its ability to regulate both protein turnover and non-proteolytic signalling functions, ubiquitin protein conjugation has been implicated in the control of multiple cellular processes, including protein localization, cell cycle control, transcription regulation, DNA damage repair, and endocytosis. Ubiquitin metabolism enzymes have been identified as either oncogenes or tumor suppressors in a variety of cancers. Given that ubiquitin metabolism is governed by enzymes-E1, E2, E3, E4, deubiquitinases (DUBs), and the proteasome- the system as a whole is ripe for target and drug discovery in cancer. Of the ubiquitin/proteasome system components, the E3's and DUBs can recognize substrates with the most specificity, and are thus of key interest as drug targets in cancer. This review examines the molecular role in cancer, relevant substrates, and potential for pharmacologic development, of E3's and DUBs that have been associated thus far with human malignancies as oncogenes or tumor suppressors.

Key words:

• ubiquitin
• E3
• cancer
• DUB
• ligase
• proteasome

Acknowledgements

The authors would like to thank R. Kulikov and M. Straza for providing comments on the manuscript. S.R.G. was supported by CA107532 from NCI. The content of this paper is solely the responsibility of the authors and does not necessarily represent the official views of NCI or NIH.

Figures and Tables

Figure 1 The enzyme cascade of the ubiquitin/proteasome system. Catalytic ubiquitin conjugating and deconjugating enzymes are pictured. Inhibitors have been characterized for all the Ub metabolism enzymes and the proteasome, as noted, except for E4s. The separation of monoubiquitination and polyubiquitination into two steps requiring two enzymes occurs for certain substrates, but as indicated, many substrates are effectively polyubiquitinated by a single E3 enzyme.

Table 1 E3's and cancer

Table 2 DUBs and cancer