The extrinsic apoptotic pathway is a fundamental means for inducing and executing apoptosis in the cell. The central signaling platform of this pathway is the death inducing signaling complex (DISC). DISC formation is triggered by an extracelluar signal and initiates the activation of caspase-8, inducing the caspase cascade and ultimately causing the demise of the doomed cell. Not surprisingly the DISC has been implicated in several human disorders, various cancers, and is suggested to play a particularly poignant role in hepatoma, cancer drug toxicity and the negative effects of alcohol abuse on the liver. This proposal aims to elucidate the mechanism of DISC formation by focusing on the prominent Fas/FADD/caspase-8 DISC. Despite a plethora of data the exact mechanism of DISC formation, that is the nature of the switch which prompts uncomplexed Fas, FADD and caspase-8 to form a death inducing signaling platform, remains elusive. We have developed a hypothesis identifying a conformational change in FADD from a latent closed form into an active open form as the key event in DISC formation. We propose a comprehensive investigation of the DISC using a unique combination of structural, biochemical and cell biology techniques to determine the mechanism of DISC formation and test our hypothesis. This work represents the missing link between the information available and a complete understanding of the DISC. Additionally this research will be paramount for the development of drugs targeting the DISC and the proposed conformational switch in FADD to foster our fight against cancer, drug toxicity and drug resistance.

Public Health Relevance

The death inducing signaling complex (DISC) is the central signaling platform in the initiation of programmed cell death by extracellular factors. Our research is designed to elucidate the mechanism of DISC formation by studying the prototypical Fas/FADD/caspase-8 DISC and to test our hypothesis, that the key event in DISC formation is a conformational switch in FADD. Since the DISC represents a prime target for homeostasis and proliferation in liver cells, it is an ideal candidate for drug development against hepatocellular carcinoma and the damaging effect of alcohol abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA017238-05
Application #
8249513
Study Section
Gastrointestinal Cell and Molecular Biology Study Section (GCMB)
Program Officer
Dunty, Jr, William
Project Start
2008-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2014-03-31
Support Year
5
Fiscal Year
2012
Total Cost
$408,944
Indirect Cost
$194,837
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Lechtenberg, Bernhard C; Mace, Peter D; Riedl, Stefan J (2014) Structural mechanisms in NLR inflammasome signaling. Curr Opin Struct Biol 29:17-25
Proell, Martina; Gerlic, Motti; Mace, Peter D et al. (2013) The CARD plays a critical role in ASC foci formation and inflammasome signalling. Biochem J 449:613-21
Mace, Peter D; Wallez, Yann; Egger, Michael F et al. (2013) Structure of ERK2 bound to PEA-15 reveals a mechanism for rapid release of activated MAPK. Nat Commun 4:1681
Kantevari, Srinivas; Yempala, Thirumal; Yogeeswari, Perumal et al. (2011) Synthesis and antitubercular evaluation of amidoalkyl dibenzofuranols and 1H-benzo[2,3]benzofuro[4,5-e][1,3]oxazin-3(2H)-ones. Bioorg Med Chem Lett 21:4316-9
Pop, Cristina; Oberst, Andrew; Drag, Marcin et al. (2011) FLIP(L) induces caspase 8 activity in the absence of interdomain caspase 8 cleavage and alters substrate specificity. Biochem J 433:447-57
Gonzalez-Lopez, Marcos; Welsh, Kate; Finlay, Darren et al. (2011) Design, synthesis and evaluation of monovalent Smac mimetics that bind to the BIR2 domain of the anti-apoptotic protein XIAP. Bioorg Med Chem Lett 21:4332-6
Mace, Peter D; Riedl, Stefan J (2010) Molecular cell death platforms and assemblies. Curr Opin Cell Biol 22:828-36
Bolze, Alexandre; Byun, Minji; McDonald, David et al. (2010) Whole-exome-sequencing-based discovery of human FADD deficiency. Am J Hum Genet 87:873-81
Wachmann, Katherine; Pop, Cristina; van Raam, Bram J et al. (2010) Activation and specificity of human caspase-10. Biochemistry 49:8307-15
Scott, Fiona L; Stec, Boguslaw; Pop, Cristina et al. (2009) The Fas-FADD death domain complex structure unravels signalling by receptor clustering. Nature 457:1019-22

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