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Event: 2244
Key Event Title
Altered Stress Response Signaling
Short name
Biological Context
Level of Biological Organization |
---|
Molecular |
Cell term
Organ term
Key Event Components
Process | Object | Action |
---|---|---|
cell surface receptor signaling pathway | increased |
Key Event Overview
AOPs Including This Key Event
AOP Name | Role of event in AOP | Point of Contact | Author Status | OECD Status |
---|---|---|---|---|
Deposition of energy leads to abnormal vascular remodeling | KeyEvent | Vinita Chauhan (send email) | Open for citation & comment | Under Review |
Deposition of Energy Leading to Learning and Memory Impairment | KeyEvent | Vinita Chauhan (send email) | Open for citation & comment | Under Review |
Taxonomic Applicability
Life Stages
Life stage | Evidence |
---|---|
All life stages | Moderate |
Sex Applicability
Term | Evidence |
---|---|
Unspecific | Low |
Key Event Description
Cells rely on a balance of signaling pathways to maintain their functionality and viability. These pathways integrate signals from both external and internal stressors to coordinate protective responses, thereby enhancing the cell's ability to cope with adverse conditions. Key components of these pathways include the activation of stress-responsive transcription factors such as NF-κB, p53, and AP-1, which regulate the expression of genes involved in cell cycle arrest, DNA repair, and apoptosis. DNA double-strand breaks, for instance, initiate a cascade of events involving the ataxia-telangiectasia mutated (ATM) kinase, the DNA-dependent protein kinase (DNA-PK), and the p53 pathway, ultimately leading to cell cycle arrest and repair mechanisms or apoptosis if the damage is irreparable (Kastan and Lim, 2000). Furthermore, the mitogen-activated protein kinase (MAPK) pathways, including ERK, JNK, and p38, are crucial for the cellular stress response and inflammatory processes (Dent et al., 2003).
These pathways are essential in regulating cellular survival and mediating apoptosis under various physiological and pathological conditions. Persistent signaling or a pre-existing inflammatory environment can significantly influence cell fate. For instance, the cAMP-PKA pathway, which is involved in neurotransmitter signaling, impacts synaptic plasticity and memory formation (Zhang et al., 2024). The MAPK pathway, encompassing ERK, JNK, and p38 MAP kinases, is vital for cell differentiation, proliferation, and response to stress stimuli (Arthur and Ley, 2013; Yue and Lopez, 2020). The PI3K-Akt pathway promotes cell survival and growth by inhibiting apoptotic processes and supporting metabolic functions (Manning and Cantley, 2007). The p53 pathway is a key regulator of the cellular stress response, often leading to apoptosis in the context of severe DNA damage or oxidative stress (Kruiswijk et al., 2015).
Exposure to stressors, such as radiation, can disrupt these stress response signaling pathways or lead to persistent activation. For example, the cAMP-PKA pathway can be hindered by reduced cAMP levels and impaired PKA activity, leading to decreased CREB phosphorylation (Zhang et al., 2024). The MAPK pathway is affected by external stressors through the inhibition of ERK activation and subsequent gene expression (Kim and Choi, 2010). The PI3K-Akt pathway, which is vital for cell survival, experiences reduced PI3K activity and Akt signaling, impairing mTOR-mediated protein synthesis (Glaviano et al., 2023; Martini et al., 2014). Activation of the p53 pathway in response to DNA damage can also potentially induce cellular senescence if the damage is irreparable (Ou et al., 2018). Persistent disruptions in these pathways can lead to a wide range of pathophysiological conditions, including neurodegenerative diseases, chronic inflammation, cardiovascular disease, and cancer.
Key Stress Response Pathways: Description and Components for Measurement
A broad way to measure these pathways concurrently is through the use of omics technologies, Omics technologies (Dai and Shen. 2022) involve comprehensive, high-throughput analysis of DNA, RNA, proteins, and metabolites to understand cellular functions and dynamics, offering a systems-level view of biological processes. Pathway analysis can then be used to gain insights from large amounts of omics data (Palli et al. 2019). Transcriptomics RNA sequence libraries are generated, clustering analysis is done, then sequencing for gene analysis (Qin et al. 2023). Proteins have been analyzed with proteomic analysis through LC-MS/MS analysis, bioinformatic analysis, western blot, qRT-PCR analysis or molecular docking. Metabolites are mass analyzed using the Thermo Q EXACTIVE, and then the edited data matrix is imported to Metabo Analyst for analysis (Hu et al. 2022).
Additionally, Post-translational modifications (PTMs) can also be measured using techniques such as mass spectrometry, which identifies and quantifies modifications like ubiquitination, glycosylation, and phosphorylation. Western blotting and immunoassays detect specific PTMs using antibodies tailored to particular modifications, while labeling methods can highlight modifications like acetylation and methylation. These measurements help elucidate protein function, stability, and interactions within cellular processes.
AMP-PKA Pathway:
The AMP-PKA pathway is activated by stressors which engage G protein-coupled receptors (GPCRs). GPCRs activation leads to the production of cyclic adenosine monophosphate (cAMP) by adenylyl cyclase. cAMP then goes on to activate protein kinase A (PKA), which is one of the primary kinases required for several functions in the cell such as DNA repair and initiating a response to oxidative stress (Hunter, 2000; Jessulat et al., 2021; Steinberg and Hardie, 2023). This results in PKA phosphorylating various target proteins, thereby influencing gene expression, metabolism and cell survival.
MAPK Pathway:
MAPK pathway is triggered by a variety of stressors, including growth factors, cytokines, hormones and various cellular stressors such as oxidative stress (Kim and Choi., 2010). The pathway involves a kinase cascade starting from receptor tyrosine kinases (RTKs) or GPCRs, leading to the activation of Ras, Raf, MEK, and ERK. Activated ERK then translocates to the nucleus and regulates gene expression, affecting cell growth, differentiation, and apoptosis (Morrison, 2012).
PI3K-Akt Pathway:
The PI3K-Akt pathway is activated by stressors through receptor tyrosine kinases (RTKs) or GPCRs. Activation of phosphoinositide 3-kinase (PI3K) generates phosphatidylinositol (3,4,5)-trisphosphate (PIP3), recruiting and activating Akt. Akt then phosphorylates downstream targets, resulting in promotion of cell survival, growth, and metabolism while inhibiting apoptosis (Martini et al., 2014; Jin et al., 2022).
NF-κB Pathway:
NF- κB is activated by pro-inflammatory cytokines, pathogens, and stress signals. This pathway involves the activation of IκB kinase (IKK), which phosphorylates IκB, leading to its degradation and the release of NF-κB. NF-κB then translocates to the nucleus and promotes the expression of genes involved in inflammation, immune response, and cell survival (Liu et al., 2017)
JAK-STAT Pathway:
The JAK-STAT signaling pathway is triggered by cytokines and growth factors. Janus kinases (JAKs) are then activated, which phosphorylate and activate signal transducer and activator of transcription (STAT) proteins. Activated STATs dimerize and translocate to the nucleus to regulate gene expression, impacting cell proliferation, differentiation, and immune function. This signaling pathway is involved in multiple important biological processes such as differentiation, apoptosis, cell proliferation and immune regulation (Xin et al., 2020).
HSP (Heat Shock Protein) Pathway:
HSP (Heat Shock Protein) pathway is induced by heat shock, oxidative stress, and other proteotoxic stresses. Stress signals lead to the activation of heat shock factor 1 (HSF1), which translocates to the nucleus and promotes the expression of heat shock proteins (HSPs). HSPs act as molecular chaperones, aiding in protein folding, preventing aggregation, and promoting protein degradation. These proteins can also work as danger signaling biomarkers, being secreted to the exterior of the cell in response to stress (Zininga et al., 2018)
p53 Pathway:
The p53 pathway is activated by DNA damage, oxidative stress, and other genotoxic stresses. DNA damage activates kinases like ATM and ATR, which phosphorylate and stabilize p53. p53 then regulates the expression of genes involved in cell cycle arrest, DNA repair, and apoptosis (Joerger and Fersht, 2016). p53 functions also expand to roles in development, metabolic regulation and stem cell biology.
Unfolded Protein Response (UPR):
Unfolded Protein Response (UPR) is triggered by the accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) (Hetz et al., 2020). This pathway involves sensors such as IRE1, PERK, and ATF6, which detect ER stress and activate downstream signaling pathways (Ron and Walter, 2007). UPR aims to restore ER homeostasis by enhancing protein folding capacity, degrading misfolded proteins, and reducing protein synthesis (Grootjans et al., 2016).
How It Is Measured or Detected
Pathway |
Method of Measurement |
Description |
Reference |
OECD Approved Assay |
cAMP-PKA |
ELISA |
Measures intracellular cAMP concentrations to assess activation of the cAMP-PKA pathway. |
Zhu et al., 2016 |
No |
cAMP-Glo™ Assay |
Monitors the level of intracellular cAMP in the cell with receptors that are modulated by lipid and free fatty acid agonists. |
Hu et al., 2019 |
No |
|
Western Blot |
Detects phosphorylation of PKA substrates, indicating pathway activation. |
Zhang et al., 2021 |
No |
|
Direct cAMP Enzyme Immunoassay |
Uses a cAMP polyclonal antibody to competitively bind the cAMP in the sample which has cAMP covalently bonded. |
Nogueira et al., 2015 |
No |
|
RT-PCR |
Quantifies mRNA levels of PKA-RII and PKA-C. |
Zhu et al., 2016 |
No |
|
MAPK |
Western Blot |
Detects the phosphorylation state of MAPK family members (ERK, JNK, p38), indicating activation. |
Tan et al., 2022; Xia and Tang 2023 |
No |
Immunohistochemistry |
Visualizes the activation of MAPKs (JNK and p38) in tissue sections using specific antibodies. |
Er et al., 2022 |
No |
|
qRT-PCR |
Quantifies mRNA levels of JNK, MAPK1(ERK), and MAPK14(p38) |
Xia and Tang 2023 |
No |
|
PI3K-Akt |
Western Blot |
Detects phosphorylation of proteins such as PI3K and AKT. |
Jin et al., 2022; Xia and Tang 2023; Bamodu et al., 2020 |
No |
qRT-PCR |
Quantifies mRNA levels of AKT1 and PI3K. |
Xia and Tang 2023 |
No |
|
p53 |
Western Blot |
Measures levels of p53 and its downstream target proteins to assess activation. |
Wei et al., 2024, Mendes et al. 2015 |
No |
qPCR |
Quantifies mRNA levels of p53-regulated genes such as p21, Bax, and H3K27me3. |
Wei et al., 2024 |
No |
|
Chromatin immunoprecipitation (ChIP) |
Detects p53 binding to DNA at target gene promoters. |
Vousden and Prives, 2009; Wei et al., 2024 |
No |
|
Co-immunoprecipitation (Co-IP) |
Identifies p53 protein to protein interactions. |
Wei et al., 2024 |
No |
|
Immunofluorescence |
Visualizes localization and expression of p53. |
Wei et al., 2024 |
No |
|
NF-κB |
Western Blot |
Detects phosphorylation and degradation of IκBα, indicating activation of the NF-κB pathway. |
Mao et al., 2023; Meier-Soelch et al., 2021; Xia and Tang 2023 |
No |
Electrophoretic Mobility Shift Assay (EMSA) |
Measures DNA-binding activity of NF-κB to specific response elements. |
Meier-Soelch et al., 2021; Ramaswami and Hayden, 2015 |
No |
|
ELISA |
Quantifies NF-κB DNA-binding activity in nuclear extracts. |
Meier-Soelch et al., 2021 |
No |
|
JAK-STAT |
Western Blot |
Measures levels of JAK2 and STAT3 |
Broughton and Burfoot, 2001; Mao et al., 2023 |
No |
Electrophoretic Mobility Shift Assay (EMSA) |
Measures DNA-binding activity of STAT proteins to specific response elements. |
Broughton and Burfoot; Jiao et al., 2003 |
No |
|
HSP |
Western Blot |
Measures levels of heat shock proteins such as HSP70 and HSP83. |
Kaur and Kaur, 2013; Thakur et al., 2019 |
No |
ELISA |
Quantifies levels of specific heat shock proteins in cell extracts. |
Kaur and Kaur, 2013 |
No |
|
Immunofluorescence |
Visualizes localization and expression of heat shock proteins in cells. |
Thakur et al., 2019 |
No |
|
UPR |
Western Blot |
Measures levels of UPR markers such as PERK, IRE1α, ATF-6 |
Sita et al., 2023; Kennedy et al., 2015; Zheng et al., 2019 |
No |
qPCR and RT-PCR |
Quantifies mRNA levels of UPR-regulated genes such as ATF4 and CHOP. |
Kennedy et al., 2015; Zheng et al., 2019 |
No |
|
Immunofluorescence |
Visualizes localization and expression of UPR markers in cells. |
Zheng et al., 2019 |
No |
Domain of Applicability
Taxonomic applicability: Altered stress response signaling is applicable to all animals as cell signaling occurs among animal cells. This includes vertebrates such as humans, mice and rats (Nair et al., 2019).
Life stage applicability: This key event is not life stage specific.
Sex applicability: This key event is not sex specific.
Evidence for perturbation by a stressor: Multiple studies show that signaling pathways can be disrupted by many types of stressors including ionizing radiation and altered gravity (Cheng et al., 2020; Coleman et al., 2021; Su et al., 2020; Yentrapalli et al., 2013).
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