Ubiquitin-mediated Regulation of Apoptosis

Ubiquitin is a protein modifier that is conjugated to target proteins either as a single moiety or as chains, branching from lysine residues within the ubiquitin moiety. Over the past years, an increasing number of ubiquitin-ligases and ubiquitin-deconjugating enzymes have been identified to modulate cell survival by degradative and non-degradative means. Mutations that affect ubiquitin-mediated signalling are tightly linked to various human pathologies including cancer. Unravelling how the ubiquitin-signal is built up, torn down and ‘read’ will be critical to understanding cellular processes such as endocytic trafficking, NF-kB signalling, gene expression, DNA repair and apoptosis.

The key aim of the lab is to elucidate how the ubiquitin-message is used as a versatile tool to modulate the cellular response to apoptosis. Over the past few years, it has become evident that certain members of the Inhibitor of APoptosis (IAP) protein family function as E3 ubiquitin ligases that are frequently over-expressed in cancer and contribute to tumour cell survival, chemo-resistance, disease progression and poor prognosis. Consistently, inactivation of IAPs results in apoptosis of several types of cancer indicating that these cells are addicted to IAPs for their survival.

Although best known for their ability to regulate caspases, IAPs also influence Ubiquitin-dependent signalling pathways such as activation of NF-kB. In particular, cIAP1 and cIAP2, which synergize with c-Myc in oncogenesis, regulate TNFa-mediated signalling and sensitivity to TRAIL-induced cell death. Moreover, they seem to contribute to cancer-related inflammation that fuels tumour growth and disease progression. Currently, little is known regarding the detailed molecular mechanisms through which cIAP1/2 contribute to cell survival and tumour growth.

We are using a combination of genetically tractable model systems and molecular tools to study the role of IAPs in ubiquitin-dependent survival signalling. Unravelling how IAPs contributes to ubiquitin-mediated cell survival and NF-kB signalling is critically important because aberrant Ubiquitin-mediated signalling frequently contributes to tumour formation. A better understanding of the process that controls apoptosis will provide a rational basis for the development of novel therapeutic strategies aimed at selectively killing cancer cells.

Interested to contribute to these or related projects? Drop me an e-mail (pmeier@icr.ac.uk). We might have a vacancy or, in case you can secure your own funding, still find some bench space in our lab.