The Walter and Eliza Hall Institute of Medical Research

Dr Grant Dewson

Details

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Division: Cell Signalling and Cell Death

Research Overview

The focus of our laboratory is the process by which cells die by apoptosis. Apoptotic cell death is essential for normal development and a functioning immune system.

Without appropriate control, diseases including cancer and neurodegenerative disorders can develop. Critical regulators of apoptosis are the Bcl-2 proteins.

Two of these, Bak and Bax, kill cells by damaging the powerhouses of the cell, the mitochondria, but how they do so is unclear. Furthermore, how their deadly activity is restrained in healthy cells and unleashed following a death stimulus is controversial. My lab aims to clarify these important issues using classical and innovative cell biology and biochemical approaches.

The long-term aim of our research is to exploit this knowledge to develop new tools to interrogate Bak and Bax function in disease and identify novel ways by which apoptosis can be therapeutically manipulated. Such therapies represent potentially valuable treatments of diseases including cancer, neurodegenerative disorders such as Parkinson’s disease and certain autoimmune conditions.

Research Interests

• Elucidating how Bak and Bax are activated in response to apoptotic stimuli
• Understanding how Bak and Bax damage mitochondria to cause cell death

Selected Publications

1. Westphal D, Dewson G, Czabotar PE, Kluck RM. Molecular biology of Bax and Bak activation and action. Biochim Biophys Acta. 2010 Dec 30. Epub ahead of print. PMID: 21195116
2. Lazarou M, Stojanovski D, Frazier AE, Kotevski A, Dewson G, Craigen WJ, Kluck RM, Vaux DL, Ryan MT. Inhibition of Bak activation by VDAC2 is dependent on the Bak transmembrane anchor. J Biol Chem. 2010 Nov 19;285(47):36876-83. PMID: 20851889
3. Dewson G, Kratina T, Czabotar P, Day CL, Adams JM, Kluck RM. Bak activation for apoptosis involves oligomerization of dimers via their α6 helices. Mol Cell. 2009 Nov 25;36(4):696-703. PMID: 19941828
4. Dewson G and Kluck RM. Mechanisms of mitochondrial outer membrane permeabilisation in apoptosis. J Cell Science. 2009 Aug 15;122(16):2801-2808. PMID: 19795525
5. Dewson G, Kratina T, Sim HW, Puthalakath H, Colman PM and Kluck RM. To trigger apoptosis Bak exposes its BH3 domain and homo-dimerizes via BH3:groove interactions. Mol Cell. 2008 May 9;30(3):369-380. PMID: 18471982
6. Uren RT, Dewson G*, Chen L, Coyne SC, Huang DCS, Adams JM, and Kluck RM. Mitochondrial permeabilization relies on BH3 ligands engaging multiple prosurvival Bcl-2 relatives, not Bak. J Cell Biol. 2007 Apr23;177(2):277-87. *Joint first author. PMID: 17452531
7. Willis SN, Chen L, Dewson G, Wei A, Naik E, Fletcher JI, Adams JM, and Huang DCS. Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins. Genes Dev. 2005 Jun 1;19(11):1294-305. PMID: 15901672
8. Uren RT, Dewson G, Bonzon C, Lithgow T, Newmeyer DD, Kluck RM. Mitochondrial release of pro-apoptotic proteins: electrostatic interactions can hold cytochrome c but not Smac/DIABLO to mitochondrial membranes. J Biol Chem. 2004 Jan 21;280(3):2266-74. PMID: 15537572
9. Dewson G, Snowden RT, Almond J, Dyer MJS, Cohen, GM. Conformational change and mitochondrial translocation of Bax accompany proteasome inhibitor-induced apoptosis of chronic leukemic cells. Oncogene. 2003 May 1;22(17):2643-54. PMID: 12730678
10. Dewson G, Cohen GM, Wardlaw AJ. Interleukin-5 inhibits translocation of Bax to the mitochondria, cytochrome c release, and activation of caspases in human eosinophils. Blood. 2001 Oct 1;98(7):2239-47. PMID: 11568012

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Current Laboratory Members

Faculty Member: Grant Dewson, BSc(Hons) PhD Leicester UK

Research Assistant: Stephen Ma, BSc(Hons) Melbourne

Research Assistant: Robert Ninnis, BBiolSci LaT

Research Assistant: Iris Tan BSc(Hons) Melb

Research Assistant: Laura Raiti