The Walter and Eliza Hall Institute of Medical Research

Dr Ruth Kluck

Details

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Division: Molecular Genetics of Cancer

Research Overview

Normal cell turnover occurs via the mitochondrial pathway of apoptotic cell death. This cell death is regulated by the Bcl-2 family of proteins, with either Bak or Bax needed for the crucial step of mitochondrial permeabilisation. We aim to delineate how Bak and Bax become active to form the apoptotic pore in the mitochondrial outer membrane, and how pore formation is blocked by pro-survival Bcl-2 family relatives.

Defining these events at the molecular level will help understand how cells decide to live or die, which is fundamental to our understanding of several pathological conditions including cancer and degenerative diseases.

Two pro-apoptotic members, Bak and Bax, can permeabilise the mitochondrial outer membrane. Members of the Bcl-2 protein family contribute to cancer development and are promising therapeutic targets, but developing such agents requires clarifying further how these proteins commits cells to apoptosis.

We are investigating the molecular mechanisms of apoptotic cell death, with a particular interest in identifying how the Bcl-2 protein family regulates mitochondrial permeabilisation. The crucial step of mitochondrial permeabilisation requires either of the pro-apoptotic Bcl-2 members, Bak or Bax, yet it remains poorly understood how they become active and induce the membrane perforation, and how they are blocked by their pro-survival relatives.

We employ a series of biochemical and cell biology approaches to determine how Bak and Bax change conformation to form the apoptotic pore within the mitochondrial outer membrane. Other analyses aim to clarify how Bak and Bax are held in check by the pro-survival regulators such as Bcl-xL and Mcl-1.

Research Interests

• What are the important conformation changes in Bak and Bax that allow pore formation in mitochondria during apoptosis?
• Bak and Bax regulation by other Bcl-2 family proteins

Selected Publications

1. Czabotar PE, Westphal D, Dewson G, Ma S, Hockings C, Fairlie WD, Lee EF, Yao S, Robin AY, Smith BJ, Huang DC, Kluck RM, Adams JM, Colman PM. Cell. 2013 Jan 31; 152(3):519-531. PMID: 23374347
2. Tran VH, Bartolo R, Westphal D, Alsop A, Dewson G, Kluck RM. Cell Death Dis. 2013 Jan 10; 4:e452. PMID: 23303126
3. Dewson G, Ma S, Frederick P, Hockings C, Tan I, Kratina T, Kluck RM. Cell Death Differ. 2012 Apr; 19(4):661-670. PMID: 22015607
4. Westphal D, Dewson G, Czabotar PE, Kluck RM.  Molecular biology of Bax and Bak activation and action.  Biochim Biophys Acta. 2011 Apr; 1813(4):521-531. PMID: 21195116
   
5. Dewson G, Kratina T, Czabotar P, Day CL, Adams JM, Kluck RM.  Bak activation for apoptosis involves oligomerization of dimers via their alpha6 helices.  Mol Cell. 2009 Nov 25;36(4):696-703. PMID 19941828
6. Dewson G, Kluck RM. Mechanisms by which Bak and Bax permeabilise mitochondria during apoptosis.  J Cell Sci. 2009 Aug 15;122(Pt 16):2801-8.PMID: 19795525
7. Dewson G, Kratina T, Sim HW, Puthalakath H, Adams JM, Colman PM, Kluck RM.  To trigger apoptosis, Bak exposes its BH3 domain and homodimerizes via BH3:groove interactions.  Mol Cell. 2008 May 9;30(3):369-80 PMID: 18471982
8. Uren RT, Dewson G, Chen L, Coyne SC, Huang DC, Adams JM, Kluck RM.  Mitochondrial permeabilization relies on BH3 ligands engaging multiple prosurvival Bcl-2 relatives, not Bak.  J Cell Biol. 2007 Apr 23;177(2):277-87 PMID: 17452531
9. Willis SN, Fletcher JI, Kaufmann T, van Delft MF, Chen L, Czabotar PE, Ierino H, Lee EF, Fairlie WD, Bouillet P, Strasser A, Kluck RM, Adams JM, Huang DC.  Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak.  Science. 2007 Feb 9;315(5813):856-9 PMID: 17289999
10. Kluck RM, Bossy-Wetzel E, Green DR, Newmeyer DD.  The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis.  Science. 1997 Feb 21;275(5303):1132-6 PMID: 9027315

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Current Laboratory Members

Faculty Member: Ruth Kluck, BSc PhD Qld

Postdoctoral Fellow: Amber Alsop, BSc(Hons) Syd PhD Cantab

Postdoctoral Fellow: Khatira Anwari, BBiomedSc Melb BSc(Hons) Melb PhD Mon

Postdoctoral Fellow: Rachel Uren, BSc(Hons) PhD Melb

Research Assistant: Stephanie Fennell, BBiolSc(Hons) LaT

Research Assistant: Ray Bartolo, BSc(Hons) Deakin, PhD Deakin

PhD Student: Sweta Iyer BSc Biotech Bharathiar, MSc Genomics Madurai Kamaraj

PhD Student: Colin Hockings, BSc(Hons) Cantab