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From zero to sixty: cell death signaling in the city that never sleeps

Oncogene volume 35, pages 1457–1460 (2016)Cite this article

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A meeting about cell death signaling would be incomplete without appropriate coverage of the different forms of caspase-mediated cell death. Guy Salvesen (Sanford-Burnham Institute for Medical Research, La Jolla, CA, USA) discussed the discovery and history of caspases, the evolutionarily conserved proteases of cell death, as well as the pathways for which they are required. Apoptosis, the cell death pathway defined by caspase activation, occurs when effector caspases-3/-6/-7 cleave a variety of cellular substrates resulting in the phenotypic hallmarks of apoptosis. The effector caspases can be activated downstream of two distinct pathways: extracellular signals can interact with cell-surface receptors (such as those in the TNF receptor family) and lead to accumulation and activation of initiator caspase-8. Alternatively, intrinsic cell stress (such as damage or nutrient deprivation) signals through the BCL-2 family of proteins, initiating permeabilization of the outer mitochondrial membrane (OMM), release of proteins from the inner-membrane space (cytochrome c), formation of the apoptosome, and finally, activation of initiator caspase-9 and downstream effector caspases.

Other forms of cell death include necroptosis, which occurs in the absence or restriction of caspase action, and pyroptosis, a recently defined form of cell death that utilizes alternative caspases-1/-11. Seamus Martin (Trinity College Dublin, Dublin, Ireland) discussed the consequences of cells dying through these mechanisms and the resulting uncontrolled release of internal components into the surrounding environment. Cells succumbing to unregulated methods of death create an inflammatory response when released chemokines and cytokines signal resident neutrophils and macrophages. In addition, released cellular components (ATP, DNA fragments) function as damage associated molecular patterns (DAMPs) and initiate pro-inflammatory signaling cascades through pattern recognition receptors (PRRs). However, Martin remarked that the list of cellular proteins or molecules that may act as DAMPs remains largely unexplored.

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Figure 1

Abbreviations

ATF4:

activating transcription factor 4

ATG5:

autophagy protein 5

ATG7:

autophagy protein 7

BAK:

BCL-2 homologous antagonist killer

BAX:

BCL-2 associated X protein

BCL-2:

B-cell lymphoma 2

BH:

BCL homology

BID:

BH3-intereacting domain death agonist

BIM:

BH3-interacting mediator of cell death

c-FLIP:

Cellular FLICE (FADD-like IL-1-converting enzyme)-inhibitory protein

CHOP:

C/EBP homologous protein

CYLD:

cylindromatosis

DAMP:

damage-associated molecular pattern

DR5/TRAIL-R2:

death receptor 5/TNF-related apoptosis-inducing ligand receptor 2

DUB:

deubiquitinase

DUBA/OTUD5:

deubiqutinating enzyme A/OTU (ovarian tumor) deubiquitinase 5

ER:

endoplasmic reticulum

Fgl2:

fibrinogen growth factor-like 2

GAPDH:

glyceraldehyde 3-phosphate dehydrogenase

HIF-1α:

hypoxia-induced factor-1α

IKK:

IκB kinase

IL:

interleukin

LAP:

LC3-associated phagocytosis

MAGT1:

magnesium transporter 1

MCL-1:

myeloid cell leukemia sequence 1

MDM2:

mouse double minute 2

MLKL:

mixed linage kinase domain-like protein

NEMO:

NFκB essential modulator

NFκB:

nuclear factor κ-light chain enhancer of activated B cells

NK:

natural killer

NKG2D:

natural killer group 2, member D

Nrp1:

neuropilin 1

OTULIN:

OTU DUB with linear linkage specificity

PD-1:

programmed cell death protein 1

PI3K:

phosphoinositide 3-kinase

PLC:

phospholipase C

PRR:

pattern recognition receptor

RIP1:

receptor interacting protein kinase 1

RIP3:

receptor interacting protein kinase 3

RORγT:

RAR-related orphan receptor gamma

Sema4a:

semaphorin 4A

TRAF2:

TNF receptor-associated factor 2

TIGIT:

T cell immunoreceptor with Ig and ITIM domains

TNF:

tumor necrosis factor

UBR5:

ubiquitin protein ligase E3 component n-recognin 5

ULK1:

unc-51 like autophagy activating kinase 1

USP7:

Ubiquitin-specific-processing protease 7.

Acknowledgements

We would like to thank the generous sponsors of the conference: Oncogene, Cell Death & Differentiation, FEBS Journal, 3i-Intelligent Imaging Innovations, Faculty of 1000 and the Nature Publishing Group; research institutions including The Icahn School of Medicine at Mount Sinai, The Tisch Cancer Institute of Mount Sinai and St Jude Children’s Research Hospital. In addition, this conference would not have been possible without the support of Drs Steven Burakoff and Ramon Parsons; the administrative team of Diana Cintron, Donna Chiodi and Evelina Berman in the Department of Oncological Sciences at the Icahn School of Medicine at Mount Sinai, New York, NY, USA; Rona and Maggie Green; Usman Hameedi, Lauren Zhao and the organizing committee: Drs Lisa Bouchier-Hayes (Baylor College of Medicine, Houston, TX, USA), Jennifer Martinez (NIH/NIEHS, Bethesda, MD, USA), Gavin McStay (New York Institute of Technology, New York, NY, USA), Andrew Oberst (University of Washington, Seattle, WA, USA), and Stephen Tait (University of Glasgow/The Beatson Institute for Cancer Research, Glasgow, UK).

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Authors and Affiliations

  1. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    J D Gelles, R Elkholi, M N Serasinghe, M P A Luna-Vargas & J E Chipuk

  2. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    J D Gelles, R Elkholi, M N Serasinghe, M P A Luna-Vargas & J E Chipuk

  3. The Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    J D Gelles & J E Chipuk

  4. The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    J D Gelles, R Elkholi & J E Chipuk

  5. Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    M N Serasinghe & J E Chipuk

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  1. J D Gelles
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Correspondence to J E Chipuk.

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Gelles, J., Elkholi, R., Serasinghe, M. et al. From zero to sixty: cell death signaling in the city that never sleeps. Oncogene 35, 1457–1460 (2016). https://doi.org/10.1038/onc.2015.194

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