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Event: 2244

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Altered Stress Response Signaling

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help
Altered Stress Response Signaling
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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help
Level of Biological Organization
Molecular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Process Object Action
cell surface receptor signaling pathway increased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
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

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
human Homo sapiens Moderate NCBI
rat Rattus norvegicus Moderate NCBI
mouse Mus musculus Moderate NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help
Life stage Evidence
All life stages Moderate

Sex Applicability

An indication of the the relevant sex for this KE. More help
Term Evidence
Unspecific Low

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

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

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

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

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

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). 

References

List of the literature that was cited for this KE description. More help

Arthur, J. S. and S. C. Ley (2013), “Mitogen-activated protein kinases in innate immunity”, Nature Reviews Immunology, Vol. 13/9, Springer, New York, https://doi.org/10.1038/nri3495   

Bamodu, O. A. et al. (2020), “Elevated PDK1 Expression Drives PI3K/AKT/MTOR Signaling Promotes Radiation-Resistant and Dedifferentiated Phenotype of Hepatocellular Carcinoma”, Cells, Vol. 9/3, Multidisciplinary Digital Publishing Institute, Basel, https://doi.org/10.3390/cells9030746  

Broughton, N. and M. S. Burfoot (2001), “JAK-mediated phosphorylation and activation of STAT signaling proteins. Analysis by phosphotyrosine blotting and EMSA”, Methods in molecular biology (Clifton, N.J.), Vol. 124, Springer, New York, https://doi.org/10.1385/1-59259-059-4:131  

Dai, X. and L. Shen (2022), “Advances and Trends in Omics Technology Development”, Frontiers in medicine, Vol. 9, Frontiers Media, Lausanne, https://doi.org/10.3389/fmed.2022.911861   

Dent, P., et al. (2003), “MAPK pathways in radiation responses”, Oncogene, Vol. 22/37, Springer, London, https://doi.org/10.1038/sj.onc.1206701  

Er, H. et al. (2022), “Acute and Chronic Exposure to 900 MHz Radio Frequency Radiation Activates p38/JNK-mediated MAPK Pathway in Rat Testis”, Reproductive sciences (Thousand Oaks, Calif.), Vol. 29/5, Springer, New York, https://doi.org/10.1007/s43032-022-00844-y  

Glaviano, A., et al. (2023). “PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer”, Molecular cancer, Vol. 22/1, Springer, London, https://doi.org/10.1186/s12943-023-01827-6Hu  

Grootjans, J. et al. (2016), “The unfolded protein response in immunity and inflammation”, Nature reviews. Immunology, Vol. 16/8, Springer, London, https://doi.org/10.1038/nri.2016.62   

Hetz, C., K. Zhang and R. J. Kaufman (2020), “Mechanisms, regulation and functions of the unfolded protein response”, Nature reviews. Molecular cell biology, Vol 21/8, Springer, London, https://doi.org/10.1038/s41580-020-0250-z  

Hu, S. et al. (2019), “Ganoderma lucidum polysaccharide inhibits UVB-induced melanogenesis by antagonizing cAMP/PKA and ROS/MAPK signaling pathways”, Journal of cellular physiology, Vol. 234/5, John Wiley & Sons, Ltd., Hoboken, https://doi.org/10.1002/jcp.27492   

Hunter, T. (2000), “Signaling - 2000 and beyond”, Cell, Vol. 100/1, Cell Press, Cambridge, https://doi.org/10.1016/s0092-8674(00)81688-8   

Hu, X., et al. (2022), “Combining network pharmacology, RNA-seq, and metabolomics strategies to reveal the mechanism of Cimicifugae Rhizoma - Smilax glabra Roxb herb pair for the treatment of psoriasis”, Phytomedicine : international journal of phytotherapy and phytopharmacology, Vol. 105, Elsevier, Amsterdam, https://doi.org/10.1016/j.phymed.2022.154384 

Jessulat, M. et al. (2021), “The conserved Tpk1 regulates non-homologous end joining double-strand break repair by phosphorylation of Nej1, a homolog of the human XLF”, Nucleic acids research, Vol. 49/14, Oxford University Press, Oxford, https://doi.org/10.1093/nar/gkab585   

Jiao, J. et al. (2003), “Initiation and maintenance of CNTF-Jak/STAT signaling in neurons is blocked by protein tyrosine phosphatase inhibitors”, Brain research. Molecular brain research, Vol.116/1-2, Elsevier, Amsterdam, https://doi.org/10.1016/s0169-328x(03)00286-9   

Jin, Y., et al. (2022). “Activation of PI3K/AKT Pathway Is a Potential Mechanism of Treatment Resistance in Small Cell Lung Cancer”. Clinical cancer research : an official journal of the American Association for Cancer Research, Vol. 28/3, https://doi.org/10.1158/1078-0432.CCR-21-1943   

Joerger, A. C. and A. R. Fersht (2016), “The p53 Pathway: Origins, Inactivation in Cancer, and Emerging Therapeutic Approaches”, Annual review of biochemistry, Vol. 85, Annual Reviews,  

Joerger AC, Fersht AR.  (2016), "The p53 Pathway: Origins, Inactivation in Cancer, and Emerging Therapeutic Approaches", Annu Rev Biochem.  Jun 2;85:375-404. doi: 10.1146/annurev-biochem-060815-014710. Epub 2016 May 4. 

Kastan, M. B. and D. S. Lim (2000), “The many substrates and functions of ATM. Nature reviews”, Molecular cell biology, Vol. 1/3, Springer, London, https://doi.org/10.1038/35043058   

Kaur, J. and S. Kaur (2013), “ELISA and western blotting for the detection of Hsp70 and Hsp83 antigens of Leishmania donovani”, Journal of parasitic diseases: official organ of the Indian Society for Parasitology, Vol. 37/1, Springer, New York, https://doi.org/10.1007/s12639-012-0133-0   

Kennedy, D., A. Samali and R. Jäger (2015), “Methods for studying ER stress and UPR markers in human cells”, Methods in molecular biology (Clifton, N.J.), Vol. 1292, Springer, New York, https://doi.org/10.1007/978-1-4939-2522-3_1   

Kim, E. K. and E. J. Choi (2010), “Pathological roles of MAPK signaling pathways in human diseases”, Biochimica et biophysica acta, Vol. 802/4, Elsevier, Amsterdam, https://doi.org/10.1016/j.bbadis.2009.12.009  

Kim, W. et al. (2019), “Cellular Stress Responses in Radiotherapy.” Cells, Vol. 8/9, Multidisciplinary Digital Publishing Institute, Basel, https://doi.org/10.3390/cells8091105  

Kruiswijk, F., C. F. Labuschagne and K. H. Vousden (2015), “p53 in survival, death and metabolic health: a lifeguard with a licence to kill”, Nature Reviews Molecular Cell Biology, Vol. 16/7, Springer, New York, https://doi.org/10.1038/nrm4007  

Liu, T. et al. (2017), “NF-κB signaling in inflammation”, Signal transduction and targeted therapy, Vol. 2, Springer, New York, https://doi.org/10.1038/sigtrans.2017.23  

Manning, B. D., and L. C. Cantley (2007)., “AKT/PKB signaling: navigating downstream”, Cell, Vol. 129/7, Elsevier, Amsterdam, https://doi.org/10.1016/j.cell.2007.06.009  

Mao, P. et al. (2023), “CXCL5 promotes tumorigenesis and angiogenesis of glioblastoma via JAK-STAT/NF-κb signaling pathways”, Molecular biology reports, Vol. 50/10, Springer, New York, https://doi.org/10.1007/s11033-023-08671-3   

Martini, M. et al. (2014), “PI3K/AKT signaling pathway and cancer: an updated review”, Annals of medicine, Vol. 46/6, Taylor & Francis, Oxfordshire, https://doi.org/10.3109/07853890.2014.912836  

Meier-Soelch, J. et al. (2021), “Monitoring the Levels of Cellular NF-κB Activation State”, Cancers, Vol. 13/21, Multidisciplinary Digital Publishing Institute, Basel, https://doi.org/10.3390/cancers13215351  

Mendes, F., et al. (2015), “Effects of X-radiation on lung cancer cells: the interplay between oxidative stress and P53 levels”, Medical oncology (Northwood, London, England), Vol. 32/12, Springer, New York, https://doi.org/10.1007/s12032-015-0712-x  

Morrison D. K. (2012), “MAP kinase pathways”, Cold Spring Harbor perspectives in biology, Vol. 4/11, https://doi.org/10.1101/cshperspect.a011254   

Nair, A. et al. (2019), “Conceptual Evolution of Cell Signaling”, International journal of molecular sciences, Vol. 20/13, Multidisciplinary Digital Publishing Institute, Basel, https://doi.org/10.3390/ijms20133292su  

Nogueira, K. M., et al. (2015), “Evidence of cAMP involvement in cellobiohydrolase expression and secretion by Trichoderma reesei in presence of the inducer sophorose”, BMC microbiology, Vol. 15, Springer, London, https://doi.org/10.1186/s12866-015-0536-z  

Ou, H. L. and B. Schumacher (2018), “DNA damage responses and p53 in the aging process”, Blood, Vol. 131/5, https://doi.org/10.1182/blood-2017-07-746396  

Palli, R., M. G. Palshikar and J. Thakar (2019), “Executable pathway analysis using ensemble discrete-state modeling for large-scale data”, PLoS computational biology, Vol. 15/9, PLOS, San Francisco, https://doi.org/10.1371/journal.pcbi.1007317  

Qin, Y. et al. (2023), “A pan-cancer analysis of the MAPK family gene and their association with prognosis, tumor microenvironment, and therapeutic targets”, Medicine, Vol. 102/45, Wolters Kluwer, Alphen aan den Rijn, https://doi.org/10.1097/MD.0000000000035829   

Ramaswami, S. and M.S. Hayden (2015), “Electrophoretic mobility shift assay analysis of NF-κB DNA binding”, Methods in molecular biology (Clifton, N.J.), Vol. 1280, Springer, New York, https://doi.org/10.1007/978-1-4939-2422-6_1  

Ron, D., and P. Walter (2007), “Signal integration in the endoplasmic reticulum unfolded protein response”, Nature reviews. Molecular cell biology, Vol. 8/7, Springer, New York, https://doi.org/10.1038/nrm2199   

Sita, G. et al. (2023), “The Unfolded Protein Response in a Murine Model of Alzheimer's Disease: Looking for Predictors”, International journal of molecular sciences, Vol. 24/22, Multidisciplinary Digital Publishing Institute, Basel, https://doi.org/10.3390/ijms242216200   

Steinberg, G. R. and D. G. Hardie (2023), “New insights into activation and function of the AMPK”, Nature reviews. Molecular cell biology, Vol. 24/4, Springer, London, https://doi.org/10.1038/s41580-022-00547-x   

Su, Y. T. et al. (2020), “Acid sphingomyelinase/ceramide mediates structural remodeling of cerebral artery and small mesenteric artery in simulated weightless rats”, Life Sciences, Vol. 243, Elsevier, Amsterdam, https://doi.org/10.1016/j.lfs.2019.117253  

Tan, B.,et al. (2022), “Changes in the histopathology and in the proteins related to the MAPK pathway in the brains of rats exposed to pre and postnatal radiofrequency radiation over four generations”, Journal of chemical neuroanatomy, Vol.126, Elsevier, Amsterdam, https://doi.org/10.1016/j.jchemneu.2022.102187  

Thakur, S. S., et al. (2019), “Expression and localization of heat-shock proteins during skeletal muscle cell proliferation and differentiation and the impact of heat stress”, Cell stress & chaperones, Vol. 24/2, Elsevier, Amsterdam, https://doi.org/10.1007/s12192-019-01001-2  

Vousden, K. H. and C. Prives (2009), “Blinded by the Light: The Growing Complexity of p53”, Cell, Vol. 137/3, Elsevier, Amsterdam, https://doi.org/10.1016/j.cell.2009.04.037  

Wei, S. et al. (2024), “DCAF13 inhibits the p53 signaling pathway by promoting p53 ubiquitination modification in lung adenocarcinoma.” Journal of experimental & clinical cancer research: CR, Vol. 43/1, Springer, London, https://doi.org/10.1186/s13046-023-02936-2  

Xia, Z., Li, Q. and Z. Tang (2023), “Network pharmacology, molecular docking, and experimental pharmacology explored Ermiao wan protected against periodontitis via the PI3K/AKT and NF-κB/MAPK signal pathways.” Journal of ethnopharmacology, Vol. 303, Elsevier, Amsterdam, https://doi.org/10.1016/j.jep.2022.115900  

Xin, P., et al. (2020), “The role of JAK/STAT signaling pathway and its inhibitors in diseases.” International immunopharmacology, Vol. 80, Elsevier, Amsterdam, https://doi.org/10.1016/j.intimp.2020.106210 

Yentrapalli, R. et al. (2013), “The PI3K/Akt/mTOR pathway is implicated in the premature senescence of primary human endothelial cells exposed to chronic radiation”, PloS one, Vol. 8/8, PLOS, San Francisco, https://doi.org/10.1371/journal.pone.0070024  

Yue, J. and J. M. López (2020), “Understanding MAPK Signaling Pathways in Apoptosis”, International journal of molecular sciences, Vol. 21/7, Multidisciplinary Digital Publishing Institute, Basel, https://doi.org/10.3390/ijms21072346   

Zhang, H., et al. (2024), “cAMP-PKA/EPAC signaling and cancer: the interplay in tumor microenvironment.” Journal of hematology & oncology, Vol. 9/1, Springer, New York, https://doi.org/10.1186/s13045-024-01524-x   

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