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Reduced risk of apoptosis: mechanisms of stress responses

  • The many ways of apoptotic cell death
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Abstract

Apoptosis signaling pathways are integrated into a wider network of interconnected apoptotic and anti-apoptotic pathways that regulate a broad range of cell responses from cell death to growth, development and stress responses. An important trigger for anti- or pro-apoptotic cell responses are different forms of stress including hypoxia, energy deprivation, DNA damage or inflammation. Stress duration and intensity determine whether the cell’s response will be improved cell survival, due to stress adaptation, or cell death by apoptosis, necrosis or autophagy. Although the interplay between enhanced stress tolerance and modulation of apoptosis triggering is not yet fully understood, there is a substantial body of experimental evidence demonstrating that apoptosis and anti-apoptosis signaling pathways can be manipulated to trigger or delay apoptosis in vitro or in vivo. Anti-apoptotic strategies cover a broad range of approaches. These interventions include mediators that prevent apoptosis (trophic factors and cytokines), apoptosis inhibition (caspase inhibition, stimulation of anti-apoptotic or inhibition of pro-apoptotic proteins and elimination of apoptotic stimulus), adaptive stress responses (induction of maintenance and repair, caspase inactivation) and cell–cell interactions (blocking engulfment and modified micro environment). There is a consensus that preclinical efficacy and safety evaluations of anti-apoptotic strategies should be performed with protocols that simulate as closely as possible the effects of aging, gender, risk factors, comorbidities and co-medications.

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Abbreviations

AIF:

Apoptosis-inducing factor

AKT/PKB:

Protein kinase B

AMPK:

5′ AMP-activated protein kinase

APAF1:

Apoptotic protease activating factor 1

APO3L:

APO3 Ligand

ARTS:

Tumor necrosis factor receptor shedding aminopeptidase regulator

ASK1:

Apoptosis signal-regulating kinase 1

ASR:

Adaptive stress response

BAD:

BCL-2 antagonist of cell death

BAK:

BCL-2 antagonist killer

BAX:

BCL-2 associated X protein

BCL-2:

B-cell lymphoma 2

BCL-xL:

B-cell lymphoma, long isoform

BH:

BCL-2 homology domains

BH1-4:

Four BH domains

BID:

BH3-interacting domain death agonist

BIM:

BCL-2—protein 11

BRAF:

v-RAF murine sarcoma viral oncogene homolog B1

CD8+:

Antiviral T lymphocytes

c-FLIP:

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

c-FLIPshort:

Cellular FLICE-Inhibitory protein-short

CMA:

Chaperone-mediated autophagy

CSA:

Cyclosporine A

DAG:

Diacylglycerol

dUTP:

2′-Deoxyuridine 5′-triphosphate

ER:

Endoplasmic reticulum

ERK1/2:

Extracellular response kinases 1/2

ERKs:

Extracellular signal regulated kinases

FAS:

Apoptosis antigen 1

FOXO:

Forkhead box O protein

GFs:

Growth factors

GLP1:

Glucagon-like peptide-1

GS:

Glycogen synthase

GSK3:

Glycogen synthase kinase 3

HIF:

Hypoxia inducing factor

HSF:

Heat shock factors

HSP90/70:

Heat shock proteins 90/70

HTRA2:

Serine protease HTRA2:mitochondrial

IAPs:

Inhibitors of apoptosis

IGF1:

Insulin-like growth factor 1

IKK:

IκB kinase

IP3R:

Inositol 1:4:5-triphosphate receptor

IRE1α:

Inositol-requiring enzyme1α

IRES:

Internal ribosome entry site

JAK:

Janus kinase

JNK:

c-jun N terminal kinases

JNK1:

c-Jun N-terminal kinase 1

MAPK:

p44/p42 mitogen activated protein kinases

MCL-1:

Myeloid cell leukemia 1

MDM2:

Anti-apoptotic mouse double minute 2

MEK:

Mitogen-activated protein kinase kinase

miRNA:

Micro ribonucleic acid

MITO MP:

Mitochondrial membrane permeability

MITO ROS:

Mitochondrial reactive oxygen species

MKK7:

MAP kinase kinase 7

mTORC1:

Mammalian target of rapamycin complex 1

mTORC2:

Mammalian target of rapamycin complex 2

NF-κB:

Nuclear factor kappa B

NOXA:

Adult T cell leukemia-derived PMA-responsive

Nrf2:

Nuclear factor-E2-related factor 2

p53:

Transformation-related protein 53

PDK-1:

3-Phosphoinositide-dependent protein kinase 1

PI3K:

Phosphatidylinositol-4:5-bisphosphate 3-kinase

PKA:

Protein kinase A

PKBK/USK:

PtdIns-3:4:5-P3 activated kinase

PKC:

Protein kinase C

PPC:

Calcium-activated protein phosphatase calcineurin

PUMA:

p53-Upregulated modulator of apoptosis

RAF:

Rapidly accelerated fibrosarcoma protein-serine/threonine kinase

ROS:

Reactive oxygen species

S6K:

Ribosomal protein S6 kinase beta 1

SAPK:

Stress-activated protein kinases

SIRT1:

Mammalian sirtuin 1

SMAC:

Second mitochondria-derived activator of caspases

SMS1:

Ceramide utilizing sphingomyelin synthase 1

-SNO:

Nitrosothiols

STAT 3,5:

Signal transducer and activator of transcription 3:5

tBID:

Truncated BID protein

TCR:

T cell receptor

TNFα:

Tumor necrosis factor alpha

TRAIL:

TNF-related apoptosis-inducing ligand

TSC2:

Tuberous sclerosis protein 2

UPP:

Ubiquitin–proteasome pathway

UPR:

Unfolded protein response

VEGF:

Vascular endothelial growth factor

XAF1:

XIAP-associated factor 1

XIAP:

X-linked inhibitor of apoptosis protein

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Acknowledgements

I. M. is supported by Grant P3-0019 and S. R. by Grant P3-0171 funded by the Ministry of Education, Science, Culture and Sport of Republic of Slovenia.

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Authors and Affiliations

  1. Faculty of Medicine, Institute of Pathophysiology, University of Ljubljana, Zaloška 4, 1000, Ljubljana, Slovenia

    Irina Milisav & Samo Ribarič

  2. Faculty of Health Sciences, University of Ljubljana, Zdravstvena pot 5, 1000, Ljubljana, Slovenia

    Irina Milisav & Borut Poljšak

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  1. Irina Milisav
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Correspondence to Irina Milisav.

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Milisav, I., Poljšak, B. & Ribarič, S. Reduced risk of apoptosis: mechanisms of stress responses. Apoptosis 22, 265–283 (2017). https://doi.org/10.1007/s10495-016-1317-3

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