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MRC Toxicology Unit

 

Unit Programme: Molecular mechanisms of cell death

Programme Leader: Dr Marion MacFarlane

 

Cell death is a fundamental cellular response that plays a crucial role both during development and in the removal of unwanted or damaged cells following stress, injury or infection. Inappropriate cell death regulation contributes to many human diseases, including cancer and autoimmune and neurodegenerative disorders. Proteins/pathways that control cell death have also been identified as defined nodes that form key decision points to regulate the response to toxic insult.

Our Programme is aimed at understanding the fundamental mechanisms of cell death that regulate life/death decisions at the cellular level. By understanding the underlying molecular and cell biology of these processes, we aim to deliver field-changing mechanistic insights into toxicology and disease.

Our research Objectives are to develop a number of strategies including novel ‘in vitro’ reconstituted models which, combined with an integrated molecular, cell biological and proteomics-based approach, place us in a prime position to examine the molecular determinants of cell death.

In particular, we will employ cutting-edge technologies to:

1. Obtain novel insights on the regulation and molecular architecture of multiprotein signalling complexes that direct cell fate

2. Define signalling networks conferring drug-induced mitochondrial toxicity or cell survival in translational models of hepatotoxicity

3. Selectively target nodes of resistance to cell death in patient-relevant 3D tumour models.

The data generated through these integrated approaches will provide novel insights into the fundamental mechanisms of cell death that underlie the response to toxic injury, thus informing strategies to mitigate toxicity of existing therapies as well as newer agents currently under development.

 

Selected Publications

Horn S, Hughes MA, Schilling R, Sticht C, Tenev T, Ploesser M, Meier P, Sprick MR, MacFarlane M, Leverkus M†. Caspase-10 Negatively Regulates Caspase-8-Mediated Cell Death, Switching the Response to CD95L in Favor of NF-κB Activation and Cell Survival. Cell Rep. 19, 785-797 (2017).

 

Chernova T, Murphy FA, Galavotti S, Sun XM, Powley IR, Grosso S, Schinwald A, Zacarias-Cabeza J, Dudek KM, Dinsdale D, Le Quesne J, Bennett J, Nakas A, Greaves P, Poland CA, Donaldson K, Bushell M, Willis AE, MacFarlane M. Long-Fiber Carbon Nanotubes Replicate Asbestos-Induced Mesothelioma with Disruption of the Tumor Suppressor Gene Cdkn2a (Ink4a/Arf). Curr Biol. 27, 3302-3314.e6 (2017).

 

Hughes MA, Powley IR, Jukes-Jones R, Horn S, Feoktistova M, Fairall L, Schwabe John WR, Leverkus M, Cain K, MacFarlane M.  Co-operative and Hierarchical Binding of c-FLIP and Caspase-8: A Unified Model Defines How c-FLIP Isoforms Differentially Control Cell Fate.  Mol Cell 61, 834-849 (2016).

 

Horvilleur E, Sbarrato T, Hill K, Spriggs RV, Screen M, Goodrem PJ, Sawicka K, Chaplin LC, Touriol C, Packham G, Potter KN, Dirnhofer S, Tzankov A, Dyer MJ, Bushell M, MacFarlane M*, Willis AE.  A role for eukaryotic initiation factor 4B overexpression in the pathogenesis of diffuse large B-cell lymphoma. Leukemia 28, 1092-1102 (2013).

 

Dickens LS, Boyd RS, Jukes-Jones R, Hughes MA, Robinson GL, Fairall L, Schwabe JW, Cain K, MacFarlane MA new DISC Model reveals a crucial role for Caspase-8 DED chain assembly in mediating apoptotic cell death. Mol Cell 47, 291-305 (2012).

 

Feoktistova M, Geserick P, Kellert B, Dimitrova D, Langlais C, Hupe M, Cain K, Hacker G, MacFarlane M, Leverkus M. cIAPs block Ripoptosome formation, a RIP1/caspase-8 containing intracellular cell death complex differentially regulated by cFLIP isoforms. Mol Cell 43, 449-463 (2011).

 

Tenev T, Bianchi K, Darding M, Broemer M, Langlais C, Wallberg F, Zachariou A, Lopez J, MacFarlane M, Cain K, Meier P.  The Ripoptosome, a signaling platform that assembles in response to genotoxic stress and loss of IAPs. Mol Cell 43, 432-448 (2011).

 

Twiddy D, Naik S, Mistry R, Edwards J, Walker RA, Cohen GM, MacFarlane M. A TRAIL-R1-selective Ligand selectively targets Primary Breast Tumour cells for Apoptosis. Breast Cancer Res., 12 (Suppl 1): 16-19. (2010).

 

Hughes MA, Harper N, Butterworth M, Cain K, Cohen GM, MacFarlane M. Reconstitution of the Death-inducing Signaling Complex (DISC) Reveals a Substrate Switch that Determines CD95-Mediated Death or Survival. Mol Cell 35, 265-279 (2009).

Dyer MJ, MacFarlane M, Cohen GM.  Barriers to effective TRAIL-targeted therapy of malignancy. J Clin Oncol 25, 4505-4506 (2007).

 

Twiddy D, Cohen GM, MacFarlane M*, Cain K*. Caspase-7 is directly activated by the approximately 700-kDa apoptosome complex and is released as a stable XIAP-caspase-7 approximately 200-kDa complex. J. Biol. Chem., 281:3876-3888 (2006).

 

MacFarlane M, Kohlhaas SL, Sutcliffe MJ, Dyer MJ, and Cohen GM. TRAIL Receptor-Selective Mutants Signal to Apoptosis via TRAIL-R1 in Primary Lymphoid Malignancies. Cancer Res 65, 11265-11270 (2005).

 

Sun X, Butterworth MB, MacFarlane M, Dubiel W, Ciechanover A, and Cohen GM. Caspase activation inhibits proteasome function during apoptosis. Mol Cell, 14, 81-93 (2004).

 

Harper N, Hughes MA, Farrow SN, Cohen GM and MacFarlane M (2003). Protein kinase C modulates TRAIL-induced apoptosis by targeting the apical events of death receptor signalling. J. Biol. Chem., 278, 44338-44347.

 

Harper N, Farrow, SN, Kaptein A, Cohen GM, and MacFarlane M. Modulation of TRAIL-induced NF-kB activation by inhibition of apical caspase activity. J Biol Chem 276, 34743-34752 (2001).