The molecular mechanisms by which the Bcl-2 family regulates apoptosis
Final Report Abstract
With 7.6 million new cases in 2008, cancer remains a leading cause of death worldwide. Conventional treatments, including radiation and chemotherapy, typically prolong life by killing tumour cells but, unfortunately, also damage healthy tissues. Thus, there is a pressing need for more effective cancer therapeutics that reduce or eliminate side effects by targeting cellular programs perturbed in the cancer cells. One cellular program with great promise for improving cancer therapy is apoptosis, the programmed cell suicide process used by all multicellular organisms to remove unwanted and potentially dangerous cells. This program is attenuated in many, if not all, cancers to facilitate their uncontrolled growth. Apoptosis is regulated predominantly by the Bcl-2 protein family, whose members either promote or prevent cell death. Notably, novel anti-cancer drugs that switch on apoptosis in cancer cells by targeting pro-survival Bcl-2 family members are already showing promise in early clinical trials. However, novel therapeutics that instead directly activate the killer molecules of the Bcl-2 family, namely Bax and Bak, might prove even more potent. Thus, research that clarifies how these proteins become activated and provoke cell death will both illuminate a fundamental biological process and help to advance cancer therapy. The major gap in understanding of apoptosis has been how the drivers of apoptosis, Bax and Bak, convert from benign monomers into the lethal oligomers that puncture the mitochondria to elicit cellular demolition. I have investigated this challenging issue, deemed the “Holy Grail” of apoptosis research by a major review, using structural and biochemical approaches. My research has provided novel insights into how these two proteins become activated, change shape and begin to form the chains that kill cells. The results I obtained have not only made major contributions to the apoptosis field but also challenged current views. In addition, the techniques that I have developed during these studies are now being exploited in my lab to further uncover the functions of Bax and Bak. I received a Young Investigator Award at the Lorne Protein Conference and I was one of four finalists for the Bupa Health Foundation Emerging Health Researcher Awards, which led to an interview with the Health professional online radio.
Publications
- (2011). Molecular biology of Bax and Bak activation and action. Biochim Biophys Acta 1813 (4), 521-31
Westphal, D., Dewson, G., Czabotar, P.E., Kluck, R.M.
- (2013). Bak apoptotic function is not directly regulated by phosphorylation. Cell Death and Disease, Jan 10; 4: e452
Tran V., Bartolo R., Westphal D., Alsop A., Dewson G., Kluck R.M.
- (2013). Bax crystal structures reveal how BH3 domains activate Bax and nucleate its oligomerization to induce apoptosis. Cell, Jan 31; 152(3): 519-31
Czabotar P.E., Westphal D., Dewson G., Ma S., Hockings C., Fairlie W.D., Lee E.F., Yao S., Robin A.Y., Smith B.J., Huang D.C.S., Kluck R.M., Adams J.M., Colman P.M.
- (2014), Bak Core and Latch Domains Separate during Activation, and Freed Core Domains Form Symmetric Homodimers. Mol Cell Volume 55, Issue 6, 18 September 2014, Pages 938-946
Brouwer J.M., Westphal D., Dewson G., Robin A.Y., Uren R.T., Bartolo R., Thompson G.V., Colman P.M., Kluck R.M., Czabotar P.E.
(See online at https://doi.org/10.1016/j.molcel.2014.07.016) - (2014). Apoptotic pore formation is associated with in-plane insertion of Bak or Bax central helices into the mitochondrial outer membrane. PNAS September 30, 2014. 111 (39) E4076-E4085
Westphal D., Dewson G., Menard M., Frederick P., Iyer S., Bartolo R., Gibson L., Czabotar P.E., Smith B.J., Adams J.M., Kluck R.M.
(See online at https://doi.org/10.1073/pnas.1415142111) - (2014). Building blocks of the apoptotic pore: How Bax and Bak are activated and oligomerize during apoptosis. Cell Death and Differentiation, Feb 21(2); 196-205
Westphal D., Kluck R.M., Dewson G.
(See online at https://doi.org/10.1038/cdd.2013.139) - (2014). NMR studies of interactions between Bax and BH3 domaincontaining peptides in the absence and presence of CHAPS. Arch Biochem Biophys, Mar 1; 545: 33-43
Yao S., Westphal D., Babon J.J., Thompson G.V., Robin A.Y., Adams J.M., Colman P.M., Czabotar P.E.
(See online at https://doi.org/10.1016/j.abb.2014.01.003)
