Professor Pascal Meier

Ubiquitin-mediated Regulation of Cell Survival and Cancer

"Induction of cell death is a key defence strategy against the emergence of cancer, as it eradicates damaged and potentially harmful cells.”

We are attempting to resolve how cancer cells bypass cell death and survive and propagate inappropriately.

Overview
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 regulation of cell death.

Our Focus
The key aim of the laboratory is to elucidate how the ubiquitin-message is used as a versatile tool to modulate the cellular response to cell death. 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. IAPs 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 synergise with c-Myc in oncogenesis, regulate TNF∝-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.

Key to IAP function is their ability to transfer Ub to target proteins. Ub is a small protein modifier that is covalently attached to target proteins in a step-wise process that involves Ub activating enzymes (E1), Ub conjugating enzymes (E2) and Ub protein ligases (E3). E3s confer substrate specificity and enable the formation of an isopeptide linkage between the carboxyl-terminus of Ub (glycine [G]76) and the amino group of a lysine (K) residue of the substrate. Ub can be conjugated either as a single moiety or as chains of variable length. Further complexity is provided by different linkage types, as Ub moieties can be conjugated to one another via different K residues within Ub. In addition to K-mediated polyubiquitylation, Ub can also be attached to the extreme amino-terminus of Ub, creating M1-linked Ub chains in which Ub is conjugated to the initiating methionine of another Ub moiety. At least eight different types of Ub chains exist that exert distinct effects on cellular processes. Differently linked polyUb chains adopt distinct overall structures. K48-linked polyUb chains adopt a kinked topology, while the ones of K63- and M1-linked chains resemble ‘beads-on-a-string’.

Recent evidence indicates that K6-, K11-, K27-, K29-, K33- and K48-linked modifications promote degradation through recognition by the 26S proteasome, and thus regulate protein levels. This ensures normal protein turnover, as well as targeted down-regulation of signalling molecules. In contrast, mono-Ub, K63- and M1-linkages contribute to a variety of non-degradative signalling processes. K63- and M1-linked chains play scaffolding roles in signal transduction events, and are formed upon stimulation of cytokine receptors. In particular, K63- and M1-linked chains are important to activate downstream kinases required for NF-kB activation and innate immune signalling. Studies in both mammalian systems and Drosophila now reveal that IAPs control apoptotic and innate immune signalling pathways via degradative and non-degradative ubiquitylation.

Our Approach
We are using a combination of genetically tractable model systems and molecular tools to study Ub-dependent survival signalling. Unravelling how the conjugation and deconjugation of Ub to target proteins modulates cell survival and NF-kB signalling is critically important, because aberrant Ub-mediated signalling frequently contributes to tumour formation.  A better understanding of the process that controls cell death and survival will provide a rational basis for the development of novel therapeutic strategies aimed at selectively killing cancer cells.

Full information on the Ubiquitin-Mediated Regulation of Apoptosis team can be found on the Breakthrough Breast Cancer Research website

Professor Pascal Meier studied for his Diploma (Swiss equivalent to MSc) in Developmental and Molecular Biology and PhD in Molecular Biology at the University of Zürich, Switzerland.

He then moved to the London Research Institute (formally The Imperial Cancer Research Fund) at Cancer Research-UK, London to work as a postdoctoral fellow. In 2000, Pascal started his own research laboratory in the Breakthrough Research Centre based at the Chester Beatty Laboratories in the Institute of Cancer Research, London.

He is a member of the Cell Death Society and recently he was awarded membership of the European Molecular Biology Organization Young Investigator Programme.