Professor David Vaux
Division: Cell Signalling and Cell Death
Most of our cells contain mechanisms for their own self-destruction. If cells in the heart or brain activate this mechanism at the wrong time, it can increase the amount of damage in a heart attack or stroke. On the other hand, if cells fail to kill themselves when they should, they can accumulate, and eventually turn into cancers.
We study the components of this self-destruct mechanism, and the regulatory processes that govern it, at the molecular level. To do so we take a genetic approach, by using cell lines that lack genes for proteins in these pathways, and a biochemical approach, by finding out which proteins bind to each other. We have developed inducible lentiviral vectors so that we can switch normal and mutant proteins on and off within cells to determine how they influence cell survival and cell death.
Much of our research focuses on the inhibitor of apoptosis (IAP) proteins. We identified four mammalian IAPs: XIAP, cIAP1, cIAP2 and Survivin. While Survivin turned out to regulate chromosome segregation in dividing cells, the other IAPs are able to inhibit cell death, but they do so in different ways. cIAP1 and cIAP2 interact with TNF receptor-associated factors (TRAFs) 1 and 2, and together with them control activity of NF-kB family transcription factors, both in resting cell and those treated with cytokines. Through interactions with RIPK1, cIAPs can also prevent TNF from triggering cell death.
The fact that IAPs in insects are inhibited by proapoptotic proteins that bind to them prompted us to look for mammalian IAP-binding proteins, and led to the discovery of Smac/Diablo. Several pharmaceutical companies have developed so called "smac-mimetic" IAP-antagonist compounds that are able to kill certain cancer cell lines in vitro. In collaboration with one of these companies, TetraLogic Pharmaceuticals (Pennsylvania USA), we are studying how these drugs function inside the cell. We found that they cause cIAP1 to dimerise and auto-ubiquitylate, so that it is sent to the proteasome, where it is destroyed.
- Roles of RIPκ1, 2 and 3 in cell signaling and cell death
- Regulation of NF-κB, caspase 8 and p53 by CARP1 and CARP2
- Pro- and anti-cell death activities of FLIP and caspase 8
- Feltham R, Bettjeman B, Budhidarmo R, Mace PD, Shirley S, Condon SM, Chunduru SK, McKinlay MA, Vaux DL, Silke J, Day CL. SMAC-mimetics activate the E3 ligase activity of cIAP1 by promoting RING dimerisation. J Biol Chem. 2011 Mar 10 [Epub ahead of print]. PMID: 21393245
- Gentle IE, Wong WW, Evans JM, Bankovacki A, Cook WD, Khan NR, Nachbur U, Rickard J, Anderton H, Moulin M, Lluis JM, Moujalled DM, Silke J, Vaux DL. In TNF-stimulated cells, RIPK1 promotes cell survival by stabilizing TRAF2 and cIAP1, which limits induction of non-canonical NF-κB and Activation of Caspase-8. J Biol Chem. 2011 Apr 15;286(15):13282-13291. PMID: 21339290
- Lluis JM, Nachbur U, Cook WD, Gentle IE, Moujalled D, Moulin M, Wong WW, Khan N, Chau D, Callus BA, Vince JE, Silke J, Vaux DL. TAK1 is required for survival of mouse fibroblasts treated with TRAIL, and does so by NF-κB dependent induction of cFLIPL. PLoS One. 2010 Jan 8;5(1):e8620. Erratum in: PLoS One. 2010;5(12) doi: 10.1371/annotation/4e35cd59-c68f-4020-addb-18eb896112c5. PMID: 20062539
- Ahmed AU, Moulin M, Coumailleau F, Wong WW, Miasari M, Carter H, Silke J, Cohen-Tannoudji M, Vince JE, Vaux DL. CARP2 deficiency does not alter induction of NF-κB by TNFα. Curr Biol. 2009 Jan 13;19(1):R15-7; author reply R17-9. PMID: 19138581
- Vince JE, Wong WW, Khan N, Feltham R, Chau D, Ahmed AU, Benetatos CA, Chunduru SK, Condon SM, McKinlay M, Brink R, Leverkus M, Tergaonkar V, Schneider P, Callus BA, Koentgen F, Vaux DL, Silke J. IAP antagonists target cIAP1 to induce TNFα-dependent apoptosis. Cell. 2007 Nov 16;131(4):682-93. PMID: 18022363
- Verhagen AM, Silke J, Ekert PG, Pakusch M, Kaufmann H, Connolly LM, Day CL, Tikoo A, Burke R, Wrobel C, Moritz RL, Simpson RJ, Vaux DL. HtrA2 promotes cell death through its serine protease activity and its ability to antagonize inhibitor of apoptosis proteins. J Biol Chem. 2002 Jan 4;277(1):445-54. PMID: 11604410
- Silke J, Verhagen AM, Ekert PG, Vaux DL. Sequence as well as functional similarity for DIABLO/Smac and Grim, Reaper and Hid? Cell Death Differ. 2000 Dec;7(12):1275. PMID: 11270364
- Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, Reid GE, Moritz RL, Simpson RJ, Vaux DL. Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell. 2000 Jul 7;102(1):43-53. PMID: 10929712
- Uren AG, Coulson EJ, Vaux DL. Conservation of baculovirus inhibitor of apoptosis repeat proteins (BIRPs) in viruses, nematodes, vertebrates and yeasts. Trends Biochem Sci. 1998 May;23(5):159-62. PMID: 9612077
- Uren AG, Pakusch M, Hawkins CJ, Puls KL, Vaux DL. Cloning and expression of apoptosis inhibitory protein homologs that function to inhibit apoptosis and/or bind tumor necrosis factor receptor-associated factors. Proc Natl Acad Sci U S A. 1996 May 14;93(10):4974-8. PMID: 8643514
Current Laboratory Members
Faculty Member: David L Vaux MBBS BMedSci PhD Melb FAA
Senior Post-Doctoral Fellow: James Vince BSc Melb PhD Melb
Senior Post-Doctoral Fellow: Katherine Lawlor BSc Melb PhD Melb
Research Assistant: Cathrine Hall BSc LaT
Postgraduate student: Donia Moujalled BSc(Hons) LaT
Publications on Scientific Integrity
- Vaux DL. Ten rules of thumb for the presentation and interpretation of data in scientific publications Australian Biochemist 2008 August Vol 39 No 2 pp37-39
- Vaux DL. Error bars in experimental biology JCB 2007 April Vol 177 No 1 7-11
- Vaux DL, Fidler F, Cumming G. Replicates and repeats - what is the difference and is it significant? EMBO reports 2012 March 13, 291-296