• Home
• Courses
• Research
• People
• News & Events
• Resources/Facilities
• Local
• Outreach
• Vacancies
• Sitemap

• Activities
• Publications
• Postgraduates
• Opportunities

CELL SIGNALLING IN CANCER AND INFLAMMATION

Research Interests

The involvement of inflammatory-associated caspases in host defence and tumour regulation

Caspases are a family of cysteine proteases that may be divided into two groups, the apoptotic caspases and the inflammatory caspases. The inflammatory caspases (human Caspase-1, -4 and -5) have gained prominence for their critical role in mediating innate immune responses. Caspase-1 is the best characterised inflammatory caspase to date. It is activated within inflammasomes (large cytosolic multi-protein complexes) by a growing number of PAMPs and DAMPs (pathogen/danger associated molecular patterns). Once activated, Caspase-1 is responsible for the processing and activation of the potent pro-inflammatory cytokines IL-1beta and IL-18. In contrast to caspase-1, caspases-4 and -5 are less well characterised in terms of their processing, activation and function. Caspase-5 is present in the NLRP1 inflammasome, whereas caspase-4 has yet to be found within an inflammasome complex.

Specific areas of interest include:

1. Elucidating the functional roles for caspases-4 and -5 via identification of their physiological substrates.

We are currently working on a novel substrate of caspases-4 and -5 which implicates these inflammatory proteases with a specific role in host defence against bacterial infection.

2. Determining the involvement of inflammatory caspases in inflammatory bowel disease (IBD) and colorectal cancers.

There is a strong link between persistent inflammation and tumourigenesis in specific tissues, for example: chronic IBD and colorectal cancer. Recent findings reveal that, in addition to a pro-inflammatory mediator, caspase-1 may also activate tissue repair responses and tumour suppressor proteins in vivo . Thus, an investigation into the role of the inflammatory caspases in the regulation of tumourigenesis is an area that warrants more attention. Using IBD and colorectal cancer as an inflammation and tumourigenesis model, we are currently investigating the involvement of caspases-1, -4 and -5 in the inflammation observed in the gut during these disease processes.

3. Identification of novel binding partners for caspase-1 and determining the implications of these interactions.

In addition to its role in the maturation of IL-1 beta and IL-18, other functions for caspase-1 have been reported, such as its role in pyroptosis (a form of cell death). We have identified the Rab GTPase, Rab39a, as a novel trafficking adaptor linking caspase-1 to IL-1beta secretion. Rab39a was identified by a proteomic screen for caspase-1 binding proteins in the human monocytic THP-1 cell line. During this screen a number of other potentially exciting caspase-1 interactors were identified and are currently being investigated.

Financial Support

The Wellcome Trust and the Broad Medical Research Program (BMRP).

Collaborators

Prof. Luke O'Neill, School of Biochemistry & Immunology, Trinity College, Ireland.
Dr. Clare Bryant, Department of Veterinary Medicine, University of Cambridge, UK.
Dr. Tom Monie, Department of Biochemistry, University of Cambridge, UK.
Dr. Debby Laukens, Dept. of Gastroenterology, Ghent University, Belgium.
Prof. Pascale Cossart, Unité des Interactions Bactéries-Cellules, Institut Pasteur, France.
Dr. Lynda Stuart, Dept. of Paediatrics, Massachusetts General Hosp., Boston, USA.
Dr. Ed Lavelle, School of Biochemistry & Immunology, Trinity College, Ireland.

Recent Publications by the Cell Signalling in Cancer and Inflammation Group

[Top of Page]