The Walter and Eliza Hall Institute of Medical Research

Associate Professor Paul Ekert

Details

Email: .(JavaScript must be enabled to view this email address)
Division: Cell Signalling and Cell Death

Research Overview

Cytokines are molecules which allow cells to communicate with one another. When cytokines bind to receptors on the cell surface, they trigger a cascade of molecular signals that activate a range of responses. Cytokines may stimulate cell division, or block it, or cause stem cells to increase in number or differentiate. Cytokines such as interleukin-3 and GM-CSF tell cells to stay alive, and prevent them activating an intrinsic cellular self-destruct process called “apoptosis”.

We are interested in the way the cytokine survival messages control the apoptosis machinery. We want to characterise this pathway, molecule by molecule, from the cytokine receptor to the apoptosis destruction machinery, and to understand how, when cytokine messages are blocked, apoptosis is initiated. Our goal is to understand how aberrations in these pathways can lead to the development of malignancies, such as myeloid leukaemia.

We also focus on the role played by a group of genes call “Hox genes” in cancer. A subgroup of Hox genes regulate blood stem cells, and how they form mature blood cells. Certain Hox genes are often found to be switched on inappropriately in leukaemia cells. We have developed ways in which we can turn particular Hox genes on and off in cultured cells at will. We are currently focusing on HoxB8, HoxA9 and the Nup98-HoxA9 fusion protein, which is not normally produced, but is found in leukaemias.

We are exploring how these genes cause leukaemia by regulating cell survival, proliferation and differentiation. As Hox proteins regulate other genes, a major goal is to identify those genes specifically regulated by cancer-associated Hox proteins, and to validate whether Hox proteins can be therapeutically targeted to treat leukaemia.

Research Interests

• Understanding the molecular signal cascade which is activated by IL-3
• How does AKT signaling regulate cell survival?
• Analysis of Hox gene function in myeloid progenitor cells
• Inducible oncogenes

Selected Publications

1. Kok CH, Brown AL, Ekert PG, D'Andrea RJ. Gene expression analysis reveals HOX gene upregulation in trisomy 8 AML. Leukemia. 2010 Jun;24(6):1239-43. Epub 2010 Apr 29. PMID: 20428200
2. Jabbour AM, Daunt CP, Green BD, Vogel S, Gordon L, Lee RS, Silke N, Pearson RB, Vandenberg CJ, Kelly PN, Nutt SL, Strasser A, Borner C, Ekert PG. Myeloid progenitor cells lacking p53 exhibit delayed up-regulation of Puma and prolonged survival after cytokine deprivation. Blood. 2010 Jan 14;115(2):344-52. Epub 2009 Nov 17. PMID: 19965665
3. Brumatti G, Salmanidis M, Ekert PG. Crossing paths: interactions between the cell death machinery and growth factor survival signals. Cell Mol Life Sci. 2010 May;67(10):1619-30. Epub 2010 Feb 16. PMID: 20157838
4. Jabbour AM, Heraud JE, Daunt CP, Kaufmann T, Sandow J, O'Reilly LA, Callus BA, Lopez A, Strasser A, Vaux DL, Ekert PG. Puma indirectly activates Bax to cause apoptosis in the absence of Bid or Bim. Cell Death Differ. 2009 Apr;16(4):555-63. Epub 2008 Dec 12. PMID: 19079139
5. Hercus TR, Thomas D, Guthridge MA, Ekert PG, King-Scott J, Parker MW, Lopez AF. The granulocyte-macrophage colony-stimulating factor receptor: linking its structure to cell signaling and its role in disease. Blood. 2009 Aug 13;114(7):1289-98. Epub 2009 May 12. PMID: 19436055
6. Mason KD, Carpinelli MR, Fletcher JI, Collinge JE, Hilton AA, Ellis S, Kelly PN, Ekert PG, Metcalf D, Roberts AW, Huang DC, Kile BT. Programmed anuclear cell death delimits platelet life span. Cell. 2007 Mar 23;128(6):1173-86. PMID: 17382885
7. Kaufmann T, Tai L, Ekert PG, Huang DC, Norris F, Lindemann RK, Johnstone RW, Dixit VM, Strasser A. The BH3-only protein bid is dispensable for DNA damage- and replicative stress-induced apoptosis or cell-cycle arrest. Cell. 2007 Apr 20;129(2):423-33. PMID: 17448999
8. Ekert PG, Jabbour AM, Manoharan A, Heraud JE, Yu J, Pakusch M, Michalak EM, Kelly PN, Callus B, Kiefer T, Verhagen A, Silke J, Strasser A, Borner C, Vaux DL. Cell death provoked by loss of interleukin-3 signaling is independent of Bad, Bim, and PI3 kinase, but depends in part on Puma. Blood. 2006 Sep 1;108(5):1461-8. Epub 2006 May 16. PMID: 16705087
9. Ekert PG, Read SH, Silke J, Marsden VS, Kaufmann H, Hawkins CJ, Gerl R, Kumar S, Vaux DL. Apaf-1 and caspase-9 accelerate apoptosis, but do not determine whether factor-deprived or drug-treated cells die. J Cell Biol. 2004 Jun 21;165(6):835-42. PMID: 15210730
10. 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

Click here to view more PubMed publications

Current Laboratory Members

Faculty Member: Paul Ekert MB.BS, PhD Melbourne FRACP

Senior Postdoctoral Fellow: Anissa Jabbour, BSc(Hons) PhD Melbourne

Senior Postdoctoral Fellow: Gabriela Brumatti PhD

Postdoctoral Fellow: Jarrod Sandow BSc(Hons) Adelaide

Postgraduate Student: Marika Salmanidis BSc(Hons) Melbourne

Postgraduate Student: Benjamin Green BSc(Hons) Melbourne

Postgraduate Student: Pratiti Bandopadhayay MBBS Melbourne FRACP

Postgraduate Student: Dimitra Masouras BSc(Hons) Melbourne

Research Assistant: Carmel Daunt BSc(Hons) Melbourne

Research Assistant: Chris Riffkin BSc(Hons) LaTrobe

Research Assistant: Natasha Silke Zurich