Cell Death and Survival Pathways Involving ATM Protein Kinase

Cell death is the ultimate form of cellular dysfunction, and is induced by a wide range of stresses including genotoxic stresses. During genotoxic stress, two opposite cellular reactions, cellular protection through DNA repair and elimination of damaged cells by the induction of cell death, can occur in both separate and simultaneous manners. ATM (ataxia telangiectasia mutated) kinase (hereafter referred to as ATM) is a protein kinase that plays central roles in the induction of cell death during genotoxic stresses. It has long been considered that ATM mediates DNA damage-induced cell death through inducing apoptosis. However, recent research progress in cell death modality is now revealing ATM-dependent cell death pathways that consist of not only apoptosis but also necroptosis, ferroptosis, and dysfunction of autophagy, a cellular survival mechanism. In this short review, we intend to provide a brief outline of cell death mechanisms in which ATM is involved, with emphasis on pathways other than apoptosis.

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Genetic Regulation of RIPK1 and Necroptosis

Annual Review of Genetics ◽

10.1146/annurev-genet-071719-022748 ◽

2021 ◽

Vol 55 (1) ◽

pp. 235-263

Author(s):

Daichao Xu ◽

Chengyu Zou ◽

Junying Yuan

Keyword(s):

Cell Death ◽

Protein Kinase ◽

Genetic Regulation ◽

Caspase 8 ◽

Inflammatory Signaling ◽

Interacting Protein ◽

Multiple Factors ◽

Cell Death Pathways ◽

Upstream Regulator ◽

Multiple Cell

The receptor-interacting protein kinase 1 (RIPK1) is recognized as a master upstream regulator that controls cell survival and inflammatory signaling as well as multiple cell death pathways, including apoptosis and necroptosis. The activation of RIPK1 kinase is extensively modulated by ubiquitination and phosphorylation, which are mediated by multiple factors that also control the activation of the NF-κB pathway. We discuss current findings regarding the genetic modulation of RIPK1 that controls its activation and interaction with downstream mediators, such as caspase-8 and RIPK3, to promote apoptosis and necroptosis. We also address genetic autoinflammatory human conditions that involve abnormal activation of RIPK1. Leveraging these new genetic and mechanistic insights, we postulate how an improved understanding of RIPK1 biology may support the development of therapeutics that target RIPK1 for the treatment of human inflammatory and neurodegenerative diseases.

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The ATM protein kinase: regulating the cellular response to genotoxic stress, and more

Nature Reviews Molecular Cell Biology ◽

10.1038/nrm3546 ◽

2013 ◽

Vol 14 (4) ◽

pp. 197-210 ◽

Cited By ~ 900

Author(s):

Yosef Shiloh ◽

Yael Ziv

Keyword(s):

Protein Kinase ◽

Cellular Response ◽

Genotoxic Stress ◽

Atm Protein

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Protein Kinase D Regulates Cell Death Pathways in Experimental Pancreatitis

Frontiers in Physiology ◽

10.3389/fphys.2012.00060 ◽

2012 ◽

Vol 3 ◽

Cited By ~ 30

Author(s):

Jingzhen Yuan ◽

Yannan Liu ◽

Tanya Tan ◽

Sushovan Guha ◽

Ilya Gukovsky ◽

...

Keyword(s):

Cell Death ◽

Protein Kinase ◽

Experimental Pancreatitis ◽

Protein Kinase D ◽

Cell Death Pathways

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Yessotoxin activates cell death pathways independent of Protein Kinase C in K-562 human leukemic cell line

Toxicology in Vitro ◽

10.1016/j.tiv.2015.05.013 ◽

2015 ◽

Vol 29 (7) ◽

pp. 1545-1554 ◽

Cited By ~ 5

Author(s):

Andrea Fernández-Araujo ◽

Amparo Alfonso ◽

Mercedes R. Vieytes ◽

Luis M. Botana

Keyword(s):

Cell Death ◽

Protein Kinase C ◽

Protein Kinase ◽

Cell Line ◽

Leukemic Cell ◽

Leukemic Cell Line ◽

Human Leukemic Cell ◽

Cell Death Pathways ◽

Kinase C ◽

Human Leukemic Cell Line

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GSK-3: A Bifunctional Role in Cell Death Pathways

International Journal of Cell Biology ◽

10.1155/2012/930710 ◽

2012 ◽

Vol 2012 ◽

pp. 1-11 ◽

Cited By ~ 123

Author(s):

Keith M. Jacobs ◽

Sandeep R. Bhave ◽

Daniel J. Ferraro ◽

Jerry J. Jaboin ◽

Dennis E. Hallahan ◽

...

Keyword(s):

Cell Death ◽

Glycogen Synthase ◽

Molecular Target ◽

Glycogen Synthase Kinase 3 ◽

Cellular Functions ◽

Cell Death Pathways ◽

Wide Range ◽

Growth Metabolism ◽

Significant Attention

Although glycogen synthase kinase-3 beta (GSK-3β) was originally named for its ability to phosphorylate glycogen synthase and regulate glucose metabolism, this multifunctional kinase is presently known to be a key regulator of a wide range of cellular functions. GSK-3βis involved in modulating a variety of functions including cell signaling, growth metabolism, and various transcription factors that determine the survival or death of the organism. Secondary to the role of GSK-3βin various diseases including Alzheimer’s disease, inflammation, diabetes, and cancer, small molecule inhibitors of GSK-3βare gaining significant attention. This paper is primarily focused on addressing the bifunctional or conflicting roles of GSK-3βin both the promotion of cell survival and of apoptosis. GSK-3βhas emerged as an important molecular target for drug development.

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The Molecular Links between Cell Death and Inflammasome

Cells ◽

10.3390/cells8091057 ◽

2019 ◽

Vol 8 (9) ◽

pp. 1057 ◽

Cited By ~ 9

Author(s):

Kwang-Ho Lee ◽

Tae-Bong Kang

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Current Knowledge ◽

Protein Complexes ◽

Death Receptor ◽

Signaling Molecules ◽

Inflammasome Activation ◽

Cell Death Pathways ◽

Wide Range ◽

Activation Pathways

Programmed cell death pathways and inflammasome activation pathways can be genetically and functionally separated. Inflammasomes are specialized protein complexes that process pro-inflammatory cytokines, interleukin-1β (IL-1β), and IL-18 to bioactive forms for protection from a wide range of pathogens, as well as environmental and host-derived danger molecules. Programmed cell death has been extensively studied, and its role in the development, homeostasis, and control of infection and danger is widely appreciated. Apoptosis and the recently recognized necroptosis are the best-characterized forms of programmed death, and the interplay between them through death receptor signaling is also being studied. Moreover, growing evidence suggests that many of the signaling molecules known to regulate programmed cell death can also modulate inflammasome activation in a cell-intrinsic manner. Therefore, in this review, we will discuss the current knowledge concerning the role of the signaling molecules originally associated with programmed cell death in the activation of inflammasome and IL-1β processing.

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Autophagy wins the 2016 Nobel Prize in Physiology or Medicine: Breakthroughs in baker's yeast fuel advances in biomedical research

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1619876114 ◽

2016 ◽

Vol 114 (2) ◽

pp. 201-205 ◽

Cited By ~ 69

Author(s):

Beth Levine ◽

Daniel J. Klionsky

Keyword(s):

Nobel Prize ◽

Genotoxic Stress ◽

Cellular Functions ◽

Nobel Committee ◽

Genetic Studies ◽

Cellular Survival ◽

Pathogen Elimination ◽

Wide Range ◽

Health And Disease ◽

Key Steps

Autophagy is an ancient pathway in which parts of eukaryotic cells are self-digested within the lysosome or vacuole. This process has been studied for the past seven decades; however, we are only beginning to gain a molecular understanding of the key steps required for autophagy. Originally characterized as a hormonal and starvation response, we now know that autophagy has a much broader role in biology, including organellar remodeling, protein and organelle quality control, prevention of genotoxic stress, tumor suppression, pathogen elimination, regulation of immunity and inflammation, maternal DNA inheritance, metabolism, and cellular survival. Although autophagy is usually a degradative pathway, it also participates in biosynthetic and secretory processes. Given that autophagy has a fundamental role in many essential cellular functions, it is not surprising that autophagic dysfunction is associated with a wide range of human diseases. Genetic studies in various fungi, particularlySaccharomyces cerevisiae, provided the key initial breakthrough that led to an explosion of research on the basic mechanisms and the physiological connections of autophagy to health and disease. The Nobel Committee has recognized this breakthrough by the awarding of the 2016 Nobel Prize in Physiology or Medicine for research in autophagy.

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Programmed Cell Death in SARS-CoV-2 Infection: A Short Review

Journal of Respiration ◽

10.3390/jor1040021 ◽

2021 ◽

Vol 1 (4) ◽

pp. 223-228

Author(s):

Rushikesh Deshpande ◽

Chunbin Zou

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Short Review ◽

Health Concern ◽

Cell Death Pathways ◽

Global Pandemic ◽

Distinct Cell ◽

Induced Apoptosis ◽

Underlying Pathophysiology

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the latest variant in the coronavirus family, causing COVID-19, has resulted in global pandemic since early 2020 leading to severe public health concern. So far, the pandemic has caused more than 200 million infections and 4 million deaths worldwide. Most of the studies are focused on developing prevention, intervention, and therapeutic strategies. However, underlying pathophysiology of the disease is important as well, which needs further attention. Cell death is one of the major causative mechanisms that leads to severe inflammation, and it is also an a posteriori consequence of the hyperinflammatory storm that renders poor prognosis of the disease. Substantial cell death has been reported in biopsy samples from post mortem patients. Among the distinct cell death pathways, apoptosis, the regulated programmed cell death plays an important role in the pathogenesis of the disease. Understanding the role of SARS-CoV-2 infection in apoptosis is critical to linearize the pathogenesis of the virus as well as the resultant disease, that may uncover novel therapeutic targets in treatment of COVID-19 patients. Here, we review the current progress on the underlying molecular mechanism(s) of SARS-CoV-2-induced apoptosis, not only at the level of the virus but also at its individual proteins.

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