Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNIZPEA)

• DOT Name: Cyclic AMP-dependent transcription factor ATF-2 (ATF2)
• Synonyms: cAMP-dependent transcription factor ATF-2; Activating transcription factor 2; Cyclic AMP-responsive element-binding protein 2; CREB-2; cAMP-responsive element-binding protein 2; HB16; cAMP response element-binding protein CRE-BP1
• Gene Name: ATF2
• Related Disease:
  Melanoma
  Neuroblastoma
  Acute myelogenous leukaemia
  Adenocarcinoma
  Adult lymphoma
  Advanced cancer
  Alzheimer disease
  Arteriosclerosis
  Atherosclerosis
  Benign neoplasm
  Bone osteosarcoma
  Breast neoplasm
  Clear cell renal carcinoma
  Colorectal carcinoma
  Crohn disease
  Depression
  Glaucoma/ocular hypertension
  Glioma
  Head-neck squamous cell carcinoma
  Hepatocellular carcinoma
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Lymphoma
  Neoplasm
  Non-alcoholic fatty liver disease
  Osteosarcoma
  Pancreatic cancer
  Parkinson disease
  Pediatric lymphoma
  Pick disease
  Renal cell carcinoma
  Skin neoplasm
  Small lymphocytic lymphoma
  Squamous cell carcinoma
  Synovial sarcoma
  Thyroid gland carcinoma
  Type-1/2 diabetes
  Urinary bladder neoplasm
  Metastatic malignant neoplasm
  Nasopharyngeal carcinoma
  Prostate cancer
  Prostate carcinoma
  Rheumatoid arthritis
  Hepatitis C virus infection
  High blood pressure
• UniProt ID: ATF2_HUMAN
• PDB ID: 1BHI; 1T2K; 4H36; 6ZQS; 6ZR5
• Pfam ID: PF00170
• Sequence:
  MKFKLHVNSARQYKDLWNMSDDKPFLCTAPGCGQRFTNEDHLAVHKHKHEMTLKFGPARN
  DSVIVADQTPTPTRFLKNCEEVGLFNELASPFENEFKKASEDDIKKMPLDLSPLATPIIR
  SKIEEPSVVETTHQDSPLPHPESTTSDEKEVPLAQTAQPTSAIVRPASLQVPNVLLTSSD
  SSVIIQQAVPSPTSSTVITQAPSSNRPIVPVPGPFPLLLHLPNGQTMPVAIPASITSSNV
  HVPAAVPLVRPVTMVPSVPGIPGPSSPQPVQSEAKMRLKAALTQQHPPVTNGDTVKGHGS
  GLVRTQSEESRPQSLQQPATSTTETPASPAHTTPQTQSTSGRRRRAANEDPDEKRRKFLE
  RNRAAASRCRQKRKVWVQSLEKKAEDLSSLNGQLQSEVTLLRNEVAQLKQLLLAHKDCPV
  TAMQKKSGYHTADKDDSSEDISVPSSPHTEAIQHSSVSTSNGVSSTSKAEAVATSVLTQM
  ADQSTEPALSQIVMAPSSQSQPSGS
• Function: Transcriptional activator which regulates the transcription of various genes, including those involved in anti-apoptosis, cell growth, and DNA damage response. Dependent on its binding partner, binds to CRE (cAMP response element) consensus sequences (5'-TGACGTCA-3') or to AP-1 (activator protein 1) consensus sequences (5'-TGACTCA-3'). In the nucleus, contributes to global transcription and the DNA damage response, in addition to specific transcriptional activities that are related to cell development, proliferation and death. In the cytoplasm, interacts with and perturbs HK1- and VDAC1-containing complexes at the mitochondrial outer membrane, thereby impairing mitochondrial membrane potential, inducing mitochondrial leakage and promoting cell death. The phosphorylated form (mediated by ATM) plays a role in the DNA damage response and is involved in the ionizing radiation (IR)-induced S phase checkpoint control and in the recruitment of the MRN complex into the IR-induced foci (IRIF). Exhibits histone acetyltransferase (HAT) activity which specifically acetylates histones H2B and H4 in vitro. In concert with CUL3 and RBX1, promotes the degradation of KAT5 thereby attenuating its ability to acetylate and activate ATM. Can elicit oncogenic or tumor suppressor activities depending on the tissue or cell type.
• Tissue Specificity: Ubiquitously expressed, with more abundant expression in the brain.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  cGMP-PKG sig.ling pathway (hsa04022)
  PI3K-Akt sig.ling pathway (hsa04151)
  Longevity regulating pathway (hsa04211)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  TNF sig.ling pathway (hsa04668)
  Thermogenesis (hsa04714)
  Dopaminergic sy.pse (hsa04728)
  Insulin secretion (hsa04911)
  Estrogen sig.ling pathway (hsa04915)
  Thyroid hormone synthesis (hsa04918)
  Glucagon sig.ling pathway (hsa04922)
  Aldosterone synthesis and secretion (hsa04925)
  Relaxin sig.ling pathway (hsa04926)
  Cortisol synthesis and secretion (hsa04927)
  Parathyroid hormone synthesis, secretion and action (hsa04928)
  Cushing syndrome (hsa04934)
  Growth hormone synthesis, secretion and action (hsa04935)
  Prion disease (hsa05020)
  Cocaine addiction (hsa05030)
  Amphetamine addiction (hsa05031)
  Alcoholism (hsa05034)
  Hepatitis B (hsa05161)
  Human cytomegalovirus infection (hsa05163)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Viral carcinogenesis (hsa05203)
  Chemical carcinogenesis - receptor activation (hsa05207)
• Reactome Pathway:
  HATs acetylate histones (R-HSA-3214847)
  Circadian Clock (R-HSA-400253)
  Activation of the AP-1 family of transcription factors (R-HSA-450341)
  TP53 Regulates Transcription of DNA Repair Genes (R-HSA-6796648)
  Regulation of PTEN gene transcription (R-HSA-8943724)
  Estrogen-dependent gene expression (R-HSA-9018519)
  NGF-stimulated transcription (R-HSA-9031628)
  Response of EIF2AK4 (GCN2) to amino acid deficiency (R-HSA-9633012)
  Heme signaling (R-HSA-9707616)
  Transcriptional activation of mitochondrial biogenesis (R-HSA-2151201)

Molecular Interaction Atlas (MIA) of This DOT

46 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Melanoma	DIS1RRCY	Definitive	Biomarker	[1]
Neuroblastoma	DISVZBI4	Definitive	Altered Expression	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[3]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[4]
Adult lymphoma	DISK8IZR	Strong	Genetic Variation	[5]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[6]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[7]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[8]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[8]
Benign neoplasm	DISDUXAD	Strong	Biomarker	[9]
Bone osteosarcoma	DIST1004	Strong	Genetic Variation	[10]
Breast neoplasm	DISNGJLM	Strong	Genetic Variation	[11]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[12]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[13]
Crohn disease	DIS2C5Q8	Strong	Genetic Variation	[14]
Depression	DIS3XJ69	Strong	Biomarker	[15]
Glaucoma/ocular hypertension	DISLBXBY	Strong	Biomarker	[16]
Glioma	DIS5RPEH	Strong	Biomarker	[17]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[18]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[19]
Lung cancer	DISCM4YA	Strong	Altered Expression	[20]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[20]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[11]
Lymphoma	DISN6V4S	Strong	Genetic Variation	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[21]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[22]
Osteosarcoma	DISLQ7E2	Strong	Genetic Variation	[10]
Pancreatic cancer	DISJC981	Strong	Biomarker	[13]
Parkinson disease	DISQVHKL	Strong	Biomarker	[23]
Pediatric lymphoma	DIS51BK2	Strong	Genetic Variation	[5]
Pick disease	DISP6X50	Strong	Biomarker	[24]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[12]
Skin neoplasm	DIS16DDV	Strong	Biomarker	[25]
Small lymphocytic lymphoma	DIS30POX	Strong	Biomarker	[26]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[27]
Synovial sarcoma	DISEZJS7	Strong	Biomarker	[28]
Thyroid gland carcinoma	DISMNGZ0	Strong	Altered Expression	[29]
Type-1/2 diabetes	DISIUHAP	Strong	Altered Expression	[30]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[21]
Metastatic malignant neoplasm	DIS86UK6	moderate	Altered Expression	[31]
Nasopharyngeal carcinoma	DISAOTQ0	moderate	Biomarker	[32]
Prostate cancer	DISF190Y	moderate	Biomarker	[33]
Prostate carcinoma	DISMJPLE	moderate	Biomarker	[33]
Rheumatoid arthritis	DISTSB4J	moderate	Genetic Variation	[34]
Hepatitis C virus infection	DISQ0M8R	Limited	Biomarker	[35]
High blood pressure	DISY2OHH	Limited	Biomarker	[36]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cyclic AMP-dependent transcription factor ATF-2 (ATF2) decreases the response to substance of Cisplatin.	[66]

11 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Cyclic AMP-dependent transcription factor ATF-2 (ATF2).	[37]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Cyclic AMP-dependent transcription factor ATF-2 (ATF2).	[42]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the phosphorylation of Cyclic AMP-dependent transcription factor ATF-2 (ATF2).	[43]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the phosphorylation of Cyclic AMP-dependent transcription factor ATF-2 (ATF2).	[48]
Sevoflurane	DMC9O43	Approved	Sevoflurane increases the phosphorylation of Cyclic AMP-dependent transcription factor ATF-2 (ATF2).	[51]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the phosphorylation of Cyclic AMP-dependent transcription factor ATF-2 (ATF2).	[54]
NCX-4016	DMOX1CU	Phase 2	NCX-4016 affects the phosphorylation of Cyclic AMP-dependent transcription factor ATF-2 (ATF2).	[55]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Cyclic AMP-dependent transcription factor ATF-2 (ATF2).	[57]
Tributylstannanyl	DMHN7CB	Investigative	Tributylstannanyl increases the phosphorylation of Cyclic AMP-dependent transcription factor ATF-2 (ATF2).	[60]
Arachidonic acid	DMUOQZD	Investigative	Arachidonic acid increases the phosphorylation of Cyclic AMP-dependent transcription factor ATF-2 (ATF2).	[61]
Aminohippuric acid	DMUN54G	Investigative	Aminohippuric acid increases the phosphorylation of Cyclic AMP-dependent transcription factor ATF-2 (ATF2).	[63]

19 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Cyclic AMP-dependent transcription factor ATF-2 (ATF2).	[38]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cyclic AMP-dependent transcription factor ATF-2 (ATF2).	[39]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Cyclic AMP-dependent transcription factor ATF-2 (ATF2).	[40]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Cyclic AMP-dependent transcription factor ATF-2 (ATF2).	[41]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Cyclic AMP-dependent transcription factor ATF-2 (ATF2).	[44]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Cyclic AMP-dependent transcription factor ATF-2 (ATF2).	[45]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Cyclic AMP-dependent transcription factor ATF-2 (ATF2).	[46]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Cyclic AMP-dependent transcription factor ATF-2 (ATF2).	[47]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Cyclic AMP-dependent transcription factor ATF-2 (ATF2).	[49]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Cyclic AMP-dependent transcription factor ATF-2 (ATF2).	[45]
Sertraline	DM0FB1J	Approved	Sertraline increases the expression of Cyclic AMP-dependent transcription factor ATF-2 (ATF2).	[50]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the activity of Cyclic AMP-dependent transcription factor ATF-2 (ATF2).	[52]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Cyclic AMP-dependent transcription factor ATF-2 (ATF2).	[53]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Cyclic AMP-dependent transcription factor ATF-2 (ATF2).	[58]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Cyclic AMP-dependent transcription factor ATF-2 (ATF2).	[59]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Cyclic AMP-dependent transcription factor ATF-2 (ATF2).	[41]
Microcystin-LR	DMTMLRN	Investigative	Microcystin-LR increases the expression of Cyclic AMP-dependent transcription factor ATF-2 (ATF2).	[62]
OXYBENZONE	DMMZYX6	Investigative	OXYBENZONE increases the expression of Cyclic AMP-dependent transcription factor ATF-2 (ATF2).	[64]
Linalool	DMGZQ5P	Investigative	Linalool increases the expression of Cyclic AMP-dependent transcription factor ATF-2 (ATF2).	[65]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
PIPERINE	DMYEAB1	Phase 1/2	PIPERINE decreases the localization of Cyclic AMP-dependent transcription factor ATF-2 (ATF2).	[56]

References

• [1] PKC phosphorylation regulates the mitochondrial translocation of ATF2 in ischemia-induced neurodegeneration.BMC Neurosci. 2018 Nov 29;19(1):76. doi: 10.1186/s12868-018-0479-z.
• [2] The thyroid hormone receptor is a suppressor of ras-mediated transcription, proliferation, and transformation.Mol Cell Biol. 2004 Sep;24(17):7514-23. doi: 10.1128/MCB.24.17.7514-7523.2004.
• [3] Genome-wide characterization of lncRNAs in acute myeloid leukemia.Brief Bioinform. 2018 Jul 20;19(4):627-635. doi: 10.1093/bib/bbx007.
• [4] p38MAPK family isoform p38 and activating transcription factor 2 are associated with the malignant phenotypes and poor prognosis of patients with ovarian adenocarcinoma.Pathol Res Pract. 2017 Oct;213(10):1282-1288. doi: 10.1016/j.prp.2017.08.003. Epub 2017 Aug 25.
• [5] Sensitisation of c-MYC-induced B-lymphoma cells to apoptosis by ATF2.Oncogene. 2014 Feb 20;33(8):1027-36. doi: 10.1038/onc.2013.28. Epub 2013 Feb 18.
• [6] MiR-657/ATF2 Signaling Pathway Has a Critical Role in Spatholobus suberectus Dunn Extract-Induced Apoptosis in U266 and U937 Cells.Cancers (Basel). 2019 Jan 28;11(2):150. doi: 10.3390/cancers11020150.
• [7] Activating transcription factor 2 expression in the adult human brain: association with both neurodegeneration and neurogenesis.Neuroscience. 2005;133(2):437-51. doi: 10.1016/j.neuroscience.2005.02.029.
• [8] Protein Kinase C Via Activating Transcription Factor 2-Mediated CD36 Expression and Foam Cell Formation of Ly6C(hi) Cells Contributes to Atherosclerosis.Circulation. 2018 Nov 20;138(21):2395-2412. doi: 10.1161/CIRCULATIONAHA.118.034083.
• [9] Oxidative stress and MAPK involved into ATF2 expression in immortalized human urothelial cells treated by arsenic.Arch Toxicol. 2013 Jun;87(6):981-9. doi: 10.1007/s00204-013-1058-9. Epub 2013 Apr 17.
• [10] Identification of biomarkers associated with the recurrence of osteosarcoma using ceRNA regulatory network analysis.Int J Mol Med. 2019 Apr;43(4):1723-1733. doi: 10.3892/ijmm.2019.4108. Epub 2019 Feb 25.
• [11] Infrequent mutations of the activating transcription factor-2 gene in human lung cancer, neuroblastoma and breast cancer.Int J Oncol. 2002 Mar;20(3):527-31.
• [12] ATF2 predicts poor prognosis and promotes malignant phenotypes in renal cell carcinoma.J Exp Clin Cancer Res. 2016 Jul 4;35(1):108. doi: 10.1186/s13046-016-0383-2.
• [13] The activating transcription factor 2: an influencer of cancer progression.Mutagenesis. 2019 Dec 19;34(5-6):375-389. doi: 10.1093/mutage/gez041.
• [14] Intestinal DMBT1 expression is modulated by Crohn's disease-associated IL23R variants and by a DMBT1 variant which influences binding of the transcription factors CREB1 and ATF-2.PLoS One. 2013 Nov 5;8(11):e77773. doi: 10.1371/journal.pone.0077773. eCollection 2013.
• [15] ATF2, a member of the CREB/ATF family of transcription factors, in chronic stress and consequent to antidepressant treatment: animal models and human post-mortem brains.Neuropsychopharmacology. 2004 Mar;29(3):589-97. doi: 10.1038/sj.npp.1300357.
• [16] Regulation of cell death and survival pathways in experimental glaucoma.Exp Eye Res. 2007 Aug;85(2):250-8. doi: 10.1016/j.exer.2007.04.011. Epub 2007 May 13.
• [17] MiR-622 suppresses proliferation, invasion and migration by directly targeting activating transcription factor 2 in glioma cells.J Neurooncol. 2015 Jan;121(1):63-72. doi: 10.1007/s11060-014-1607-y. Epub 2014 Sep 26.
• [18] Activating transcription factor-2 in survival mechanisms in head and neck carcinoma cells.Head Neck. 2011 Nov;33(11):1586-99. doi: 10.1002/hed.21648. Epub 2010 Dec 28.
• [19] Silencing activating transcription factor 2 promotes the anticancer activity of sorafenib in hepatocellular carcinoma cells.Mol Med Rep. 2018 Jun;17(6):8053-8060. doi: 10.3892/mmr.2018.8921. Epub 2018 Apr 23.
• [20] MiR-451a suppressed cell migration and invasion in non-small cell lung cancer through targeting ATF2.Eur Rev Med Pharmacol Sci. 2018 Sep;22(17):5554-5561. doi: 10.26355/eurrev_201809_15818.
• [21] ATF2 promotes urothelial cancer outgrowth via cooperation with androgen receptor signaling.Endocr Connect. 2018 Dec 1;7(12):1397-1408. doi: 10.1530/EC-18-0364.
• [22] Dual regulation of HMGB1 by combined JNK1/2-ATF2 axis with miR-200 family in nonalcoholic steatohepatitis in mice.FASEB J. 2018 May;32(5):2722-2734. doi: 10.1096/fj.201700875R. Epub 2018 Jan 3.
• [23] Activation of the ATF2/CREB-PGC-1 pathway by metformin leads to dopaminergic neuroprotection.Oncotarget. 2017 Jul 25;8(30):48603-48618. doi: 10.18632/oncotarget.18122.
• [24] Current advances on different kinases involved in tau phosphorylation, and implications in Alzheimer's disease and tauopathies.Curr Alzheimer Res. 2005 Jan;2(1):3-18. doi: 10.2174/1567205052772713.
• [25] ATF2 - at the crossroad of nuclear and cytosolic functions.J Cell Sci. 2012 Jun 15;125(Pt 12):2815-24. doi: 10.1242/jcs.095000. Epub 2012 Jun 8.
• [26] Molecular basis of aggressive disease in chronic lymphocytic leukemia patients with 11q deletion and trisomy 12 chromosomal abnormalities.Int J Mol Med. 2007 Oct;20(4):461-9.
• [27] Overexpression of phosphorylated-ATF2 and STAT3 in cutaneous squamous cell carcinoma, Bowen's disease and basal cell carcinoma.J Dermatol Sci. 2008 Sep;51(3):210-5. doi: 10.1016/j.jdermsci.2008.04.008. Epub 2008 Jun 10.
• [28] Activating transcription factor 2 in mesenchymal tumors.Hum Pathol. 2014 Feb;45(2):276-84. doi: 10.1016/j.humpath.2013.09.003. Epub 2013 Nov 27.
• [29] Role of JNK/ATF-2 pathway in inhibition of thrombospondin-1 (TSP-1) expression and apoptosis mediated by doxorubicin and camptothecin in FTC-133 cells.Biochim Biophys Acta. 2011 May;1813(5):695-703. doi: 10.1016/j.bbamcr.2011.02.004. Epub 2011 Feb 17.
• [30] Ubiquitin fold modifier 1 activates NF-B pathway by down-regulating LZAP expression in the macrophage of diabetic mouse model.Biosci Rep. 2020 Jan 31;40(1):BSR20191672. doi: 10.1042/BSR20191672.
• [31] A Novel Pak1/ATF2/miR-132 Signaling Axis Is Involved in the Hematogenous Metastasis of Gastric Cancer Cells.Mol Ther Nucleic Acids. 2017 Sep 15;8:370-382. doi: 10.1016/j.omtn.2017.07.005. Epub 2017 Jul 8.
• [32] Epstein-Barr virus-encoded EBNA1 modulates the AP-1 transcription factor pathway in nasopharyngeal carcinoma cells and enhances angiogenesis in vitro.J Gen Virol. 2008 Nov;89(Pt 11):2833-2842. doi: 10.1099/vir.0.2008/003392-0.
• [33] SPOP promotes ATF2 ubiquitination and degradation to suppress prostate cancer progression.J Exp Clin Cancer Res. 2018 Jul 11;37(1):145. doi: 10.1186/s13046-018-0809-0.
• [34] Rheumatoid arthritis reprograms circadian output pathways.Arthritis Res Ther. 2019 Feb 6;21(1):47. doi: 10.1186/s13075-019-1825-y.
• [35] Long noncoding RNA #32 contributes to antiviral responses by controlling interferon-stimulated gene expression.Proc Natl Acad Sci U S A. 2016 Sep 13;113(37):10388-93. doi: 10.1073/pnas.1525022113. Epub 2016 Aug 31.
• [36] Activation of cardiac c-Jun NH(2)-terminal kinases and p38-mitogen-activated protein kinases with abrupt changes in hemodynamic load.Hypertension. 2001 May;37(5):1222-8. doi: 10.1161/01.hyp.37.5.1222.
• [37] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [38] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [39] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [40] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [41] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [42] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [43] Combination of arsenic trioxide and Dasatinib: a new strategy to treat Philadelphia chromosome-positive acute lymphoblastic leukaemia. J Cell Mol Med. 2018 Mar;22(3):1614-1626.
• [44] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [45] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [46] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [47] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [48] p38 MAPK/PP2Ac/TTP pathway on the connection of TNF- and caspases activation on hydroquinone-induced apoptosis. Carcinogenesis. 2013 Apr;34(4):818-27. doi: 10.1093/carcin/bgs409. Epub 2013 Jan 3.
• [49] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [50] Sertraline induces endoplasmic reticulum stress in hepatic cells. Toxicology. 2014 Aug 1;322:78-88. doi: 10.1016/j.tox.2014.05.007. Epub 2014 May 24.
• [51] Sevoflurane-mediated activation of p38-mitogen-activated stresskinase is independent of apoptosis in Jurkat T-cells. Anesth Analg. 2008 Apr;106(4):1150-60, table of contents. doi: 10.1213/ane.0b013e3181683d37.
• [52] Resveratrol stimulates cyclic AMP response element mediated gene transcription. Mol Nutr Food Res. 2016 Feb;60(2):256-65. doi: 10.1002/mnfr.201500607. Epub 2015 Oct 28.
• [53] Novel carbocyclic curcumin analog CUR3d modulates genes involved in multiple apoptosis pathways in human hepatocellular carcinoma cells. Chem Biol Interact. 2015 Dec 5;242:107-22.
• [54] Activation of extracellular signal-regulated kinase and c-Jun-NH(2)-terminal kinase but not p38 mitogen-activated protein kinases is required for RRR-alpha-tocopheryl succinate-induced apoptosis of human breast cancer cells. Cancer Res. 2001 Sep 1;61(17):6569-76.
• [55] Nitric oxide-donating aspirin inhibits colon cancer cell growth via mitogen-activated protein kinase activation. J Pharmacol Exp Ther. 2006 Jan;316(1):25-34. doi: 10.1124/jpet.105.091363. Epub 2005 Sep 16.
• [56] Piperine is a potent inhibitor of nuclear factor-kappaB (NF-kappaB), c-Fos, CREB, ATF-2 and proinflammatory cytokine gene expression in B16F-10 melanoma cells. Int Immunopharmacol. 2004 Dec 20;4(14):1795-803. doi: 10.1016/j.intimp.2004.08.005.
• [57] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [58] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [59] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [60] Inhibition of PP2A and the consequent activation of JNK/c-Jun are involved in tributyltin-induced apoptosis in human amnionic cells. Environ Toxicol. 2013 Jul;28(7):390-400. doi: 10.1002/tox.20730. Epub 2011 May 27.
• [61] Arachidonic acid induces Fas and FasL upregulation in human leukemia U937 cells via Ca2+/ROS-mediated suppression of ERK/c-Fos pathway and activation of p38 MAPK/ATF-2 pathway. Toxicol Lett. 2009 Dec 15;191(2-3):140-8. doi: 10.1016/j.toxlet.2009.08.016. Epub 2009 Aug 29.
• [62] Protein phosphatase 2A inhibition and subsequent cytoskeleton reorganization contributes to cell migration caused by microcystin-LR in human laryngeal epithelial cells (Hep-2). Environ Toxicol. 2017 Mar;32(3):890-903. doi: 10.1002/tox.22289. Epub 2016 Jul 9.
• [63] Nanomolar levels of PAHs in extracts from urban air induce MAPK signaling in HepG2 cells. Toxicol Lett. 2014 Aug 17;229(1):25-32. doi: 10.1016/j.toxlet.2014.06.013. Epub 2014 Jun 6.
• [64] Chromatin modifiers: A new class of pollutants with potential epigenetic effects revealed by in vitro assays and transcriptomic analyses. Toxicology. 2023 Jan 15;484:153413. doi: 10.1016/j.tox.2022.153413. Epub 2022 Dec 26.
• [65] Linalool preferentially induces robust apoptosis of a variety of leukemia cells via upregulating p53 and cyclin-dependent kinase inhibitors. Toxicology. 2010 Jan 31;268(1-2):19-24. doi: 10.1016/j.tox.2009.11.013. Epub 2009 Nov 14.
• [66] The activation of c-Jun NH2-terminal kinase (JNK) by DNA-damaging agents serves to promote drug resistance via activating transcription factor 2 (ATF2)-dependent enhanced DNA repair. J Biol Chem. 2003 Jun 6;278(23):20582-92. doi: 10.1074/jbc.M210992200. Epub 2003 Mar 27.