The Walter and Eliza Hall Institute of Medical Research

Professor Jerry Adams

Details

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Division: Molecular Genetics of Cancer

Research Overview

The research of my laboratory is focused on the molecular control of apoptosis by the Bcl-2 family of proteins, how this control is disrupted in cancer and how apoptotic mechanisms can be exploited to improve cancer therapy.

Background

Most apoptotic pathways converge on the mitochondrion, where the interactions of three sub-families of the Bcl-2 protein family determine whether the cell will live or die (Adams and Cory, Oncogene, 2007). While Bcl-2 itself and its closest relatives (eg Bcl-xL and Mcl-1) promote cell survival, two other factions instead promote cell death. Members of the first pro-death faction share with the wider family only the short BH3 domain, by which they engage their pro-survival relatives and initiate apoptotic signalling. Subsets of these ‘BH3-only proteins’ are activated by different cytotoxic signals, including those used in cancer therapy. Subsequently, Bax and Bak, which comprise the other pro-death faction, change conformation and form oligomers that permeabilize the mitochondrial membrane and thereby free proteins such as cytochrome c, which then activate the proteases (caspases) that dismantle the cell.

My research, often together with senior colleagues such as David Huang, Andreas Strasser, Suzanne Cory, Philippe Bouillet and Ruth Kluck, is addressing major unresolved issues about the molecular control of apoptosis. Together with other laboratories in the Division and Structural Biology colleagues, we are also interested in exploring the potential of targeting pro-survival Bcl-2 proteins as a new approach to cancer therapy.

Research Projects

Molecular Control of Apoptosis

Targeting Pro-survival Bcl-2 Proteins

Major Publications

1. Fletcher, J I, Meusburger, S., Hawkins, C. J., Riglar, D. T., Lee, E. F., Fairlie, W. D., *Huang, D. C., *Adams, J. M. 2008. *Joint senior authors
   Apoptosis is triggered when prosurvival Bcl-2 proteins cannot restrain
   Bax. Proc Natl Acad Sci U S A. 105(47): 18081-7. PMID: 18981409
   Inaugural article. Faculty of 1000 ‘Recommended’.
2. Dewson, G, Kratina, T, Sim, H.W, Puthalakath, H, Adams, J.M, Colman, P.M, Kluck, R.M. 2008.
   To trigger apoptosis Bak exposes its BH3 domain and homodimerizes via BH3: groove interactions.
   Molecular Cell. 30(3):369-380. PMID: 18471982
3. Michalak, EM, Villunger, A, *Adams, JM and *Strasser, A. 2008. *Joint senior authors
   In several cell types tumour suppressor p53 induces apoptosis largely via Puma but Noxa can contribute.
   Cell Death Diff. 15:1019-1029.PMID: 18259198
4. Kelly P N, Dakic A, *Adams J M, *Nutt S L and *Strasser A. 2007.
   Tumor growth need not be driven by rare cancer stem cells.
   Science 317:337. *Joint senior authors (113 citations) Faculty of 1000 'Must Read' PMID: 17641192
5. Uren, R.T., Dewson, G., Chen, L., Coyne, S.C., Huang, D.C.S., Adams, J.M. and Kluck, R.M.
   Mitochondrial permeabilization relies on BH3 ligands engaging multiple pro-survival Bcl-2 relatives, not
   Bak. Journal of Cell Biology, 177(2): 277-287, 2007. (22 citations)  PMID: 17452531
6. Willis S N, Fletcher J I, Kaufmann T, van Delft M F, Chen L, Czabotar P E, Ierino H, Lee E F, Fairlie W D, Bouillet P, Strasser A, Kluck R M, *Adams J M and *Huang D C. 2007.
   Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak.
   Science 315:856-859. *Joint senior authors (205 citations) Faculty of 1000 'Must Read' PMID: 17289999
7. van Delft M F, Wei A H, Mason K D, Vandenberg C J, Chen L, Czabotar P E, Willis S N, Scott C L, Day C L, Cory S, *Adams J M, *Roberts A W and *Huang D C S. 2006.
   The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized.
   Cancer Cell. 10:389-399. *Joint senior authors (129 citations) Faculty of 1000 'Must Read' PMID: 17097561
8. Willis S N, Chen L, Dewson G, Wei A, Naik E, Fletcher J I, *Adams J M and *Huang D C. 2005.
   Pro-apoptotic Bak is sequestered by Mc1-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins.
   Genes Dev. 19:1294-1305. *joint senior authors (297 citations) Faculty of 1000 'Must Read' PMID: 15901672
9. Chen L, Willis S N, Wei A, Smith B J, Fletcher J I, Hinds M G, Colman P M, Day C L, *Adams J M and *Huang D C S. 2005.
   Differential targeting of pro-survival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function.
   Mol. Cell 17:393-403. *joint senior authors (452 citations) Faculty of 1000 'Must Read' PMID: 15694340
10. Villunger A, Michalak E M, Coultas L, Müllauer F, Böck G, Ausserlechner M J, Adams J M and Strasser A. 2003.
    p53- and drug-induced apoptotic responses mediated by BH3-only proteins Puma and Noxa.
    Science 302:1036-1038. (456 citations) Faculty of 1000 'Must Read' PMID: 14500851

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Current Laboratory Members

Faculty Member: Jerry Adams, BSc Emory PhD Harvard FAA FRS

Postdoctoral Fellow: Grant Dewson (with Ruth Kluck)

Postdoctoral Fellow: Sabrina Giavara (with David Huang)

Postdoctoral Fellow: Priscilla Kelly (with Andreas Strasser)

Postdoctoral Fellow: Dana Westphal

Postdoctoral Fellow: Monica Yabal (with David Huang)

Research Assistant: Leonie Gibson