Mapping the TNFR1 interactome
Project type
Honours
| Supervisor(s) | Division | |
| (Primary) | Cell Signalling and Cell Death | .(JavaScript must be enabled to view this email address) |
Dr Andrew Webb (Co-supervisor) |
Personalised Medicine and Systems Biology | .(JavaScript must be enabled to view this email address) |
Details of project
Inducible lentiviral expression vectors will be generated for known components of the TNF-R1 signalling complex. Inducible cell lines will be generated and lysates prepared in the presence and absence of TNF. A high affinity GFP reagent will be used to precipitate protein complexes containing the component of interest. The complexes will then be analysed by Mass Spectrometry which should identify known and possibly unknown proteins within these complexes.
This project will use cutting-edge techniques and reagents including inducible lentiviral expression vectors, high affinity GFP reagents and Mass Spectrometry and would be an ideal preparation for a PhD project. The area of research has enormous medical relevance and findings might eventually be translated into better treatments.
While simple in concept, and therefore highly likely to readily provide the minimum amount of data for a good Honours project, it also has enormous potential to increase in scale. It would therefore suit any student interested in becoming proficient in a wide range of techniques and in excelling.
Research interests
TNF-R1 signalling is one of the most studied and best understood signal transduction pathways because of its master role in a host of chronic inflammatory diseases. Even though blocking TNF signalling has been proven to treat chronic inflammatory diseases such as rheumatoid arthritis, Crohn's disease and cancer (anti-TNF reagents generated global sales of over US$13 billion in 2007), there are many aspects of TNF signaling which are poorly understood.
In the midst of the worldwide research effort on this pathway our lab has been able to identify new roles for previously identified molecules (Vince 2007, Vince 2009, Haas 2009, Wong 2010, Feltham 2010) and have identified three new molecules that form a ubiquitin E3 ligase complex that regulates the strength of TNF-R1 signalling (Haas 2009, Gerlach 2011).
Our aim is to continue to identify new players and further understand the role of existing molecules in TNF signalling.
Selected publications
- Feltham et al. Journal of Biological Chemistry 2010. TNF signaling, but not TWEAK - triggered cIAP1 (cellular inhibitor of apoptosis protein 1) degradation, requires cIAP1 RING dimerization and E2 binding.
- Gerlach et al Nature 2011. Linear ubiquitination prevents inflammation and regulates immune signaling.
- Haas et al. Molecular Cell 2009. Recruitment of the linear ubiquitin chain assembly complex stabilizes the TNF-R1 signaling complex and is required for TNF-mediated gene induction.
- Vince et al. Cell 2007. IAP antagonists target cIAP1 to induce TNF [alpha]-dependent apoptosis.
- Vince et al. Journal of Biological Chemistry 2009. TRAF2 must bind to cellular inhibitors of apoptosis for tumor necrosis factor (TNF) to efficiently activate NF- B and to prevent TNF-induced apoptosis.
- Wong et al. Cell Death & Differentiation 2009. RIPK1 is not essential for TNFR1-induced activation of NF-κB.
Research theme
Chronic inflammatory diseases
Scientific discipline
- Biochemistry
- Cell Biology
- Molecular Biology
Keywords
TNF, rheumatoid arthritis, Crohn’s disease, cancer