Ubiquitin-mediated signalling in apoptosis and cancer
Supervisor(s): Professor Pascal Meier
Breakthrough Breast Cancer Research Centre
Ubiquitin-mediated Regulation of Apoptosis Team
View full details of this PhD Studentship in PDF format
Summary
K63-linked di-Ubiquitin
The aim of this PhD project is to identify how the ubiquitin (Ub)-message is used to modulate the cellular response to apoptosis. Mutations that affect apoptosis and Ub-mediated survival signalling are tightly linked to tumorigenesis [1] and chronic, cancer-related inflammation (also called para-inflammation) [2], which generates a local micro-environment that promotes the development of tumours. Unravelling how the Ub-signal is conjugated, edited and translated into cellular phenotypes that permit tumour formation will be critically important to gain a better understanding of cancer.
The covalent attachment of Ub to target is a three-step process that culminates in the conjugation of Ub either as a single moiety (monoubiquitylation), or as poly-Ub chains [3]. For polyubiquitylation, the Ub molecules are generally linked through the lysine (K) residue at position 48 and 63 of Ub [4]. The different types of poly-Ub chains have different effects; with K48-linked chains being recognised by the proteasome leading to degradation of the modified protein, and monoubiquitylation as well as K63-linkages contributing to non-degradative signalling processes [3].
The diverse signalling outcomes are dependent on protein-interactions between the ubiquitylated protein and Ub-binding proteins, called ubiquitin-receptors [5]. Ub-receptors carry specialised Ub-binding domains (UBD) enabling them to recruit Ub-modified proteins to specific signalling complexes. Ub-mediated signalling is subject to tight regulation as the Ub-message can be cleaved off by Ub-specific proteases (USPs). Currently, 84 human and 43 Drosophila USPs have been identified. However, little is currently known about their function.
The successful candidate will identify and characterise Ub-receptors and Ub-specific proteases that regulate apoptosis and cancer-related inflammation. Pilot experiments have already identified some interesting candidates, which await further analysis. Taken together, the aim of the project is to generate insight and to further our understanding in Ub-mediated regulation of apoptosis and para-inflammation. A better understanding of the machinery that executes apoptosis and the mechanisms that control para-inflammation will provide the basis for more rational cancer therapies in the future.
References
- Hoeller, D., Dikic, I. (2009) Targeting the ubiquitin system in cancer therapy. Nature 458(7237), p438
- Mantovani, A., et al. (2008) Cancer-related inflammation. Nature 454(7203), p436
- Hoeller, D., et al. (2006) Ubiquitin and ubiquitin-like proteins in cancer pathogenesis. Nat Rev Cancer Vol 6, No 10, p776
- Hochstrasser, M. (2006) Lingering mysteries of ubiquitin-chain assembly. Cell Vol 124, No 1, p27
