A focus of my research program is the molecular interactions that regulate the mitochondrial pathway to apoptotic cell death. This is defining how apoptosis is tightly controlled in healthy cells, and how it becomes dysregulated in disease.
We aim to facilitate therapeutic target identification and rational design of compounds to directly manipulate the apoptotic pathway. Promoting apoptosis has applications for cancer therapy, while blocking cell death has potential as a treatment for ischaemia or degenerative diseases. This follows the paradigm that has resulted in the development of BH3 mimetic drugs, which are in clinical trials for the treatment of certain cancers.
My lab is also interested in the molecular control of mitophagy (mitochondrial quality control). Mitophagy is controlled by the E3 ubiquitin ligase Parkin, which is mutated in degenerative conditions including certain forms of Parkinson’s disease. It is also emerging as an important tumour suppressor.
We are investigating how Parkin interacts with the apoptosis machinery to co-ordinate mitochondrial quality control, how its activity influences the growth and survival of tumours, and whether this machinery represents a novel target for the treatment of cancer.
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Grant Dewson's selected work
Robust autoactivation for apoptosis by BAK but not BAX highlights BAK as an important ther..
BAX Activation: Mutations Near Its Proposed Non-canonical BH3 Binding Site Reveal Alloster..
Parkin inhibits BAK and BAX apoptotic function by distinct mechanisms during mitophagy
Displaying the 74 most recent scholarly works by Grant Dewson.
EBV BCL-2 homologue BHRF1 drives chemoresistance and lymphomagenesis by inhibiting multiple cellular pro-apoptotic proteins
Leah Fitzsimmons, Rachel Cartlidge, Catherine Chang, Nenad Sejic, Laura CA Galbraith, Chathura D Suraweera, Deborah Croom-Carter, Grant Dewson, Rosemary J Tierney, Andrew Bell, Clare Shannon-Lowe, Marco J Herold, Alan B Rickinson, Peter M Colman, David CS Huang, Andreas Strasser, Marc Kvansakul, Martin Rowe, Gemma L Kelly
Journal article | 2020 | Cell Death & Differentiation
Epstein-Barr virus (EBV), which is ubiquitous in the adult population, is causally associated with human malignancies. Like many i..
A small molecule interacts with VDAC2 to block mouse BAK-driven apoptosis
Mark F van Delft, Stephane Chappaz, Yelena Khakham, T Bui Chinh, Marlyse A Debrincat, Kym N Lowes, Jason M Brouwer, Christoph Grohmann, Phillip P Sharp, Laura F Dagley, Lucy Li, Kate McArthur, Meng-Xiao Luo, Hui San Chin, W Douglas Fairlie, Erinna F Lee, David Segal, Stephane Duflocq, Romina Lessene, Sabrina Bernard, et al.
Journal article | 2019 | Nature Chemical Biology
Activating the intrinsic apoptosis pathway with small molecules is now a clinically validated approach to cancer therapy. In contr..
BAX Activation: Mutations Near Its Proposed Non-canonical BH3 Binding Site Reveal Allosteric Changes Controlling Mitochondrial Association
Michael A Dengler, Adeline Y Robin, Leonie Gibson, Mark X Li, Jarrod J Sandow, Sweta Iyer, Andrew Webb, Dana Westphal, Grant Dewson, Jerry M Adams
Journal article | 2019 | Cell Reports
Parkin inhibits BAK and BAX apoptotic function by distinct mechanisms during mitophagy
Jonathan P Bernardini, Jason M Brouwer, Iris KL Tan, Jarrod J Sandow, Shuai Huang, Che A Stafford, Aleksandra Bankovacki, Christopher D Riffkin, Ahmad Z Wardak, Peter E Czabotar, Michael Lazarou, Grant Dewson
Journal article | 2019 | The EMBO Journal
VDAC2 enables BAX to mediate apoptosis and limit tumor development
Hui San Chin, Mark X Li, Iris KL Tan, Robert L Ninnis, Boris Reljic, Kristen Scicluna, Laura F Dagley, Jarrod J Sandow, Gemma L Kelly, Andre L Samson, Stephane Chappaz, Seong L Khaw, Catherine Chang, Andrew Morokoff, Kerstin Brinkmann, Andrew Webb, Colin Hockings, Cathrine M Hall, Andrew J Kueh, Michael T Ryan, et al.
Journal article | 2018 | Nature Communications
Mutant TRP53 exerts a target gene-selective dominant-negative effect to drive tumor development
Brandon J Aubrey, Ana Janic, Yunshun Chen, Catherine Chang, Elizabeth C Lieschke, Sarah T Diepstraten, Andrew J Kueh, Jonathan P Bernardini, Grant Dewson, Lorraine A O'Reilly, Lachlan Whitehead, Anne K Voss, Gordon K Smyth, Andreas Strasser, Gemma L Kelly
Journal article | 2018 | Genes & Development
BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis
Kate McArthur, Lachlan W Whitehead, John M Heddleston, Lucy Li, Benjamin S Padman, Viola Oorschot, Niall D Geoghegan, Stephane Chappaz, Sophia Davidson, Hui San Chin, Rachael M Lane, Marija Dramicanin, Tahnee L Saunders, Canny Sugiana, Romina Lessene, Laura D Osellame, Teng-Leong Chew, Grant Dewson, Michael Lazarou, Georg Ramm, et al.
Journal article | 2018 | Science
A critical epithelial survival axis regulated by MCL-1 maintains thymic function in mice
Reema Jain, Julie M Sheridan, Antonia Policheni, Melanie Heinlein, Luke C Gandolfo, Grant Dewson, Gordon K Smyth, Stephen N Sansom, Nai Yang Fu, Jane E Visvader, Georg A Hollander, Andreas Strasser, Daniel HD Gray
Journal article | 2017 | Blood
Conversion of Bim-BH3 from Activator to Inhibitor of Bak through Structure-Based Design
Jason M Brouwer, Ping Lan, Angus D Cowan, Jonathan P Bernardini, Richard W Birkinshaw, Mark F van Delft, Brad E Sleebs, Adeline Y Robin, Ahmad Wardak, Iris K Tan, Boris Reljic, Erinna F Lee, W Douglas Fairlie, Melissa J Call, Brian J Smith, Grant Dewson, Guillaume Lessene, Peter M Colman, Peter E Czabotar
Journal article | 2017 | Molecular Cell
Synergistic action of the MCL-1 inhibitor S63845 with current therapies in preclinical models of triple-negative and HER2-amplified breast cancer
Delphine Merino, James R Whittle, Francois Vaillant, Antonin Serrano, Jia-Nan Gong, Goknur Giner, Ana Leticia Maragno, Maia Chanrion, Emilie Schneider, Bhupinder Pal, Xiang Li, Grant Dewson, Julius Grasel, Kevin Liu, Najoua Lalaoui, David Segal, Marco J Herold, David CS Huang, Gordon K Smyth, Olivier Geneste, et al.
Journal article | 2017 | Science Translational Medicine
BAK alpha 6 permits activation by BH3-only proteins and homooligomerization via the canonical hydrophobic groove
Mark Xiang Li, Iris KL Tan, Stephen B Ma, Colin Hockings, Tobias Kratina, Michael A Dengler, Amber E Alsop, Ruth M Kluck, Grant Dewson
Journal article | 2017 | Proceedings of the National Academy of Sciences
Huntingtin Inclusions Trigger Cellular Quiescence, Deactivate Apoptosis, and Lead to Delayed Necrosis
Yasmin M Ramdzan, Mikhail M Trubetskov, Angelique R Ormsby, Estella A Newcombe, Xiaojing Sui, Mark J Tobin, Marie N Bongiovanni, Sally L Gras, Grant Dewson, Jason ML Miller, Steven Finkbeiner, Nagaraj S Moily, Jonathan Niclis, Clare L Parish, Anthony W Purcell, Michael J Baker, Jacqueline A Wilce, Saboora Waris, Diana Stojanovski, Till Bocking, et al.
Journal article | 2017 | Cell reports
Physiological restraint of Bak by Bcl-x(L) is essential for cell survival
Erinna F Lee, Stephanie Grabow, Stephane Chappaz, Grant Dewson, Colin Hockings, Ruth M Kluck, Marlyse A Debrincat, Daniel H Gray, Matthew T Witkowski, Marco Evangelista, Anne Pettikiriarachchi, Philippe Bouillet, Rachael M Lane, Peter E Czabotar, Peter M Colman, Brian J Smith, Benjamin T Kile, W Douglas Fairlie
Journal article | 2016 | Genes & Development
Characterizing Bcl-2 Family Protein Conformation and Oligomerization Using Cross-Linking and Antibody Gel-Shift in Conjunction with Native PAGE.
Journal article | 2016 | Methods in molecular biology (Clifton, N.J.)
The Bcl-2 family of proteins tightly controls the intrinsic or mitochondrial pathway of apoptosis. This family is subdivided based..
An aspartyl protease defines a novel pathway for export of Toxoplasma proteins into the host cell
Michael J Coffey, Brad E Sleebs, Alessandro D Uboldi, Alexandra Garnham, Magdalena Franco, Nicole D Marino, Michael W Panas, David JP Ferguson, Marta Enciso, Matthew T O'Neill, Sash Lopaticki, Rebecca J Stewart, Grant Dewson, Gordon K Smyth, Brian J Smith, Seth L Masters, John C Boothroyd, Justin A Boddey, Christopher J Tonkin
Journal article | 2015 | eLife
Blue Native PAGE and Antibody Gel Shift to Assess Bak and Bax Conformation Change and Oligomerization.
Journal article | 2015 | Cold Spring Harbor Protocols
Blue native PAGE (BN-PAGE) uses Coomassie dye rather than denaturing SDS to provide a negative charge to proteins for electrophore..
Bid chimeras indicate that most BH3-only proteins can directly activate Bak and Bax, and show no preference for Bak versus Bax
C Hockings, K Anwari, RL Ninnis, J Brouwer, M O'Hely, M Evangelista, MG Hinds, PE Czabotar, EF Lee, WD Fairlie, G Dewson, RM Kluck
Journal article | 2015 | Cell Death & Disease
The Functional Differences between Pro-survival and Pro-apoptotic B Cell Lymphoma 2 (Bcl-2) Proteins Depend on Structural Differences in Their Bcl-2 Homology 3 (BH3) Domains
Erinna F Lee, Grant Dewson, Marco Evangelista, Anne Pettikiriarachchi, Grace J Gold, Haoran Zhu, Peter M Colman, W Douglas Fairlie
Journal article | 2014 | Journal of Biological Chemistry
Bax targets mitochondria by distinct mechanisms before or during apoptotic cell death: a requirement for VDAC2 or Bak for efficient Bax apoptotic function
SB Ma, TN Nguyen, I Tan, R Ninnis, S Iyer, DA Stroud, M Menard, RM Kluck, MT Ryan, G Dewson
Journal article | 2014 | Cell Death & Differentiation
Apoptotic pore formation is associated with in-plane insertion of Bak or Bax central helices into the mitochondrial outer membrane
Dana Westphal, Grant Dewson, Marie Menard, Paul Frederick, Sweta Iyer, Ray Bartolo, Leonie Gibson, Peter E Czabotar, Brian J Smith, Jerry M Adams, Ruth M Kluck
Journal article | 2014 | Proceedings of the National Academy of Sciences
RIPK1 Regulates RIPK3-MLKL-Driven Systemic Inflammation and Emergency Hematopoiesis
James A Rickard, Joanne A O'Donnell, Joseph M Evans, Najoua Lalaoui, Ashleigh R Poh, TeWhiti Rogers, James E Vince, Kate E Lawlor, Robert L Ninnis, Holly Anderton, Cathrine Hall, Sukhdeep K Spall, Toby J Phesse, Helen E Abud, Louise H Cengia, Jason Corbin, Sandra Mifsud, Ladina Di Rago, Donald Metcalf, Matthias Ernst, et al.
Journal article | 2014 | Cell
Assembly of the Bak Apoptotic Pore A CRITICAL ROLE FOR THE BAK PROTEIN alpha 6 HELIX IN THE MULTIMERIZATION OF HOMODIMERS DURING APOPTOSIS
Stephen Ma, Colin Hockings, Khatira Anwari, Tobias Kratina, Stephanie Fennell, Michael Lazarou, Michael T Ryan, Ruth M Kluck, Grant Dewson
Journal article | 2013 | Journal of Biological Chemistry
Bax Crystal Structures Reveal How BH3 Domains Activate Bax and Nucleate Its Oligomerization to Induce Apoptosis
Peter E Czabotar, Dana Westphal, Grant Dewson, Stephen Ma, Colin Hockings, W Douglas Fairlie, Erinna F Lee, Shenggen Yao, Adeline Y Robin, Brian J Smith, David CS Huang, Ruth M Kluck, Jerry M Adams, Peter M Colman
Journal article | 2013 | Cell
Granzyme B triggers a prolonged pressure to die in Bcl-2 overexpressing cells, defining a window of opportunity for effective treatment with ABT-737
VR Sutton, K Sedelies, G Dewson, ME Christensen, PI Bird, RW Johnstone, RM Kluck, JA Trapani, NJ Waterhouse
Journal article | 2012 | Cell Death & Disease
Fas-mediated neutrophil apoptosis is accelerated by Bid, Bak, and Bax and inhibited by Bcl-2 and Mcl-1
Ben A Croker, Joanne A O'Donnell, Cameron J Nowell, Donald Metcalf, Grant Dewson, Kirsteen J Campbell, Kelly L Rogers, Yifang Hu, Gordon K Smyth, Jian-Guo Zhang, Michael White, Kurt Lackovic, Louise H Cengia, Lorraine A O'Reilly, Philippe Bouillet, Suzanne Cory, Andreas Strasser, Andrew W Roberts
Journal article | 2011 | Proceedings of the National Academy of Sciences of the United States of America
Maximal killing of lymphoma cells by DNA damage-inducing therapy requires not only the p53 targets Puma and Noxa, but also Bim
Lina Happo, Mark S Cragg, Belinda Phipson, Jon M Haga, Elisa S Jansen, Marco J Herold, Grant Dewson, Ewa M Michalak, Cassandra J Vandenberg, Gordon K Smyth, Andreas Strasser, Suzanne Cory, Clare L Scott
Journal article | 2010 | Blood
Interleukin 15-mediated survival of natural killer cells is determined by interactions among Bim, Noxa and Mcl-1
Nicholas D Huntington, Hamsa Puthalakath, Priscilla Gunn, Edwina Naik, Ewa M Michalak, Mark J Smyth, Hyacinth Tabarias, Mariapia A Degli-Esposti, Grant Dewson, Simon N Willis, Noboru Motoyama, David CS Huang, Stephen L Nutt, David M Tarlinton, Andreas Strasser
Journal article | 2007 | NATURE IMMUNOLOGY
Intermediate filaments control the intracellular distribution of caspases during apoptosis.
David Dinsdale, Justine C Lee, Grant Dewson, Gerald M Cohen, Marcus E Peter
Journal article | 2004 | The American Journal of Pathology
Caspases are responsible for a cascade of events controlling the disassembly of apoptotic cells. We now demonstrate that caspase-9..
Conformational change and mitochondrial translocation of Bax accompany proteasome inhibitor-induced apoptosis of chronic lymphocytic leukemic cells.
Grant Dewson, Roger T Snowden, Jason B Almond, Martin JS Dyer, Gerald M Cohen
Journal article | 2003 | Oncogene
Chemotherapy resistance remains a major clinical problem in patients with B-cell chronic lymphocytic leukemia (B-CLL). Proteasome ..
Interleukin-5 inhibits translocation of Bax to the mitochondria, cytochrome c release, and activation of caspases in human eosinophils.
G Dewson, GM Cohen, AJ Wardlaw
Journal article | 2001 | Blood
The apoptosis and subsequent clearance of eosinophils without histotoxic mediator release is thought to be crucial in the resoluti..
Interleukin-13 induces PSGL-1/P-selectin-dependent adhesion of eosinophils, but not neutrophils, to human umbilical vein endothelial cells under flow.
G Woltmann, CA McNulty, G Dewson, FA Symon, AJ Wardlaw
Journal article | 2000 | Blood
Selective eosinophil accumulation is a hallmark of diseases such as asthma. In a model of chronic eosinophilic inflammation, we ha..
Expression of Bcl-2 and its homologues in human eosinophils. Modulation by interleukin-5.
G Dewson, GM Walsh, AJ Wardlaw
Journal article | 1999 | American Journal of Respiratory Cell and Molecular Biology
The Bcl-2 family has been shown to be vital regulators of programmed cell death in numerous systems. To investigate the role of su..
A comparative study of different methods for the assessment of apoptosis and necrosis in human eosinophils.
GM Walsh, G Dewson, AJ Wardlaw, F Levi-Schaffer, R Moqbel
Journal article | 1998 | Journal of Immunological Methods
Eosinophils, prominent cells in asthmatic inflammation, undergo apoptosis or programmed cell death following deprivation of contac..
Medical Biology (W.E.H.I.)