The Walter and Eliza Hall Institute of Medical Research

Associate Professor John Silke

Details

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Division: Cell Signalling and Cell Death

Research Overview

Apoptosis or programmed cell death is a physiological process for killing cells and is critical for the normal development and function of multicellular organisms. Apoptosis is fundamentally important in preventing tumourigenesis and it is now widely acknowledged that defects in the apoptotic pathway result in increased tumour formation, with one of the seminal papers in the field coming from Australia (Strasser et al., 1990).

The effectors of the cell death program are enzymes called caspases, that degrade essential proteins within the cell and effectively digest the cell from the inside. Capsases can be regulated directly or indirectly by the so called inhibitor of apoptosis proteins (IAPs).

We are using different approaches with the ultimate aim of discovering how IAPs function and how that knowledge might be applied to deliver better anti-cancer drugs to the clinic.

Our lab collaborates with many other organisations including, Tetralogic Pharmaceuticals, Associate Professor Paul Ekert's lab in the Cell Death and Cell Signalling division, Associate Professor Catherine Day's group at the University of Otago, Professor Pascal Meier's group at the Institute of Cancer Research, Associate Professor Robert Brink's lab at the Garvan Institute.

Research Interests

• Inhibitors of apoptosis proteins (IAPs) antagonists
• Inflammation
• Necroptosis

Selected Publications

1. Nachbur U, Vince JE, O'Reilly LA, Strasser A & Silke J. Is BID required for NOD signalling? Nature. 2012; 488: E4-6; discussion E6-8. PMID: 22914170
2. Moulin M, Anderton H, Voss AK, Thomas T, Wong WW, Bankovacki A, Feltham R, Chau D, Cook W, Silke J & Vaux DL. IAPs limit activation of RIP kinases by TNF receptor 1 during development. EMBO J. 2012; 31: 1679-1691. PMID: 22327219
3. Damgaard RB, Nachbur U, Yabal M, Wong WW, Fill BK, Kastirr M, Rieser E, Rickard JA, Bankovacki A, Peschel C, Ruland J, Bekker-Jensen S, Mailand N, Kaufmann T, Strasser A, Walczak H, Silke J, Jost PJ & Gyrd-Hansen M. The ubiquitin ligase XIAP recruits LUBAC for NOD2 signaling in inflammation and innate immunity. Mol Cell. 2012; 46:746-758. PMID:22607974
4. Gerlach B, Cordier SM, Schmukle AC, Emmerich CH, Rieser E, Haas TL, Webb AI, Rickard JA, Anderton H, Wong WW, Nachbur U, Gangoda L, Warnken U, Purcell AW, Silke J & Walczak H. Linear ubiquitination prevents inflammation and regulates immune signalling. Nature. 2011; 471: 591-596. PMID: 21455173
5. Feltham R, Bettjeman B, Budhidarmo R, Mace PD, Shirley S, Condon SM, Chunduru SK, McKinlay MA, Vaux DL, Silke J & Day CL. SMAC-mimetics activate the E3 ligase activity of cIAP1 by promoting RING domain dimerisation. J Biol Chem. 2011; 286: 17015-17028. PMID: 21393245
6. Silke J & Brink R. Regulation of TNFRSF and innate immune signalling complexes by TRAFs and cIAPs. Cell Death Differ. 2010; 17: 35-45. PMID: 19680262
7. Haas TL, Emmerich CH, Gerlach B, Schmukle AC, Cordier SM, Rieser E, Feltham R, Vince J, Warnken U, Wenger T, Koschny R, Komander D, Silke J & Walczak H. Recruitment of the linear ubiquitin chain assembly complex stabilizes the TNF-R1 signaling complex and is required for TNF-mediated gene induction. Mol Cell. 2009; 36: 831-844. PMID: 20005846
8. Wong WW-L, Gentle IE, Nachbur U, Anderton H, Vaux DL & Silke J. RIPK1 is not essential for TNFR1-induced activation of NF-κB. Cell Death Differ. 2010; 17: 482-487. PMID: 1992715
9. Vince JE, Chau D, Callus B, Wong WW-L, Hawkins CJ, Schneider P, McKinlay M, Benetatos CA, Condon SM, Chunduru SK, Yeoh G, Brink R, Vaux DL & Silke J. TWEAK-FN14 signaling induces lysosomal degradation of a cIAP1-TRAF2 complex to sensitize tumor cells to TNF. J Cell Biol. 2008; 182: 171-184. PMID: 18606850
10. Vince JE, Wong WW-L, Khan N, Feltham R, Chau D, Ahmed AU, Benetatos CA, Chunduru SK, Condon SM, McKinlay M, Brink R, Leverkus M, Tergaonkar V, Schneider P, Callus BA, Koentgen F, Vaux DL & Silke J IAP Antagonists Target cIAP1 to Induce TNF-Dependent Apoptosis. Cell. 2007; 131: 682-693. PMID: 18022363

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Current Laboratory Members

Faculty Member: John Silke, LLB (King's College, London), BA (Hons) Cantab, PhD Zurich

Senior Post-Doctoral Fellow: Ueli Nachbur, PhD Bern

Senior Post-Doctoral Fellow: Najoua Lalaoui, PhD France

Postgraduate student: Nima Etemadi, BSc MSc LaT

Postgraduate student: Joseph Evans, BBiomedSc(Hons) LaT

Postgraduate student: James Rickard, BSc LaT MSc LaT

Research Assistant: Holly Anderton, BA Canterbury BSc(Hons) Canterbury

Research Assistant: Diep Chau, BSc Melb

Research Assistant: Sukhdeep Spall, BSc India MSc LaT

Research Assistant: Aleksandra Bankovacki, BSc(Hons) LaT