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 ICR, Associate Professor Robert Brink's lab at the Garvan Institute.

Research Interests

• Inhibitors of apoptosis proteins (IAPs) antagonists

Selected Publications

1. Feltham R, Moulin M, Vince JE, Mace PD, Wong WW-L, Anderton H, Day CL, Vaux DL & Silke J Tumor Necrosis Factor (TNF) Signaling, but Not TWEAK (TNF-like Weak Inducer of Apoptosis)-triggered cIAP1 (Cellular Inhibitor of Apoptosis Protein 1) Degradation, Requires cIAP1 RING Dimerization and E2 Binding. J Biol Chem. 2010; 285: 17525-17536. PMID: 20356846
2. Gerlach B. Linear ubiquitination prevents inflammation and regulates immune signalling. Nature. 2011.
3. Gyrd-Hansen M, Darding M, Miasari M, Santoro MM, Zender L, Xue W, Tenev T, da Fonseca PCA, Zvelebil M, Bujnicki JM, Lowe S, Silke J & Meier P. IAPs contain an evolutionarily conserved ubiquitin-binding domain that regulates NF-kappaB as well as cell survival and oncogenesis. Nat Cell Biol. 2008; 10: 1309-1317. PMID: 18931663
4. 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
5. Jost PJ, Grabow S, Gray D, McKenzie MD, Nachbur U, Huang DCS, Bouillet P, Thomas HE, Borner C, Silke J, Strasser A & Kaufmann T. XIAP discriminates between type I and type II FAS-induced apoptosis. Nature. 2009; 460: 1035-1039. PMID: 19626005
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. 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
8. 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
9. Vince JE, Pantaki D, Feltham R, Mace PD, Cordier SM, Schmukle AC, Davidson AJ, Callus BA, Wong WW-L, Gentle IE, Carter H, Lee EF, Walczak H, Day CL, Vaux DL & Silke J. TRAF2 must bind to cellular inhibitors of apoptosis for tumor necrosis factor (TNF) to efficiently activate NF-κB and to prevent TNF-induced apoptosis. J Biol Chem. 2009; 284: 35906-35915. PMID: 19815541
10. 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: 19927158

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Current Laboratory Members

Faculty Member: John Silke, LLB, BA Hons (cantab), PhD Zurich

Senior Post-Doctoral Fellow: Ueli Nachbur, PhD Bern

Senior Post-Doctoral Fellow: Najoua Lalaoui, PhD France

Senior Post-Doctoral Fellow: Lynn Wong, BSc Guelph, PhD Toronto

Postgraduate student: Nima Etemadi, BSc MSc LaT

Postgraduate student: Joseph Evans, BBiomedSc(Hons) LaT

Postgraduate student: Lahiru Gangoda

Postgraduate student: James Rickard, BSc LaT MSc LaT

Overseas research trainee: Richelle Spanjers

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