Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9617UO)

• DOT Name: Cyclic AMP-responsive element-binding protein 3 (CREB3)
• Synonyms: CREB-3; cAMP-responsive element-binding protein 3; Leucine zipper protein; Luman; Transcription factor LZIP-alpha
• Gene Name: CREB3
• Related Disease:
  Adult glioblastoma
  Glioblastoma multiforme
  Alzheimer disease
  Arteriosclerosis
  Atherosclerosis
  Bone osteosarcoma
  Epithelial ovarian cancer
  Fatty liver disease
  Hepatocellular carcinoma
  Metabolic disorder
  Neoplasm
  Osteosarcoma
  Ovarian cancer
  Ovarian neoplasm
  Adrenocortical insufficiency
  Advanced cancer
  Hepatitis C virus infection
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Rheumatoid arthritis
• UniProt ID: CREB3_HUMAN
• Pfam ID: PF00170
• Sequence:
  MELELDAGDQDLLAFLLEESGDLGTAPDEAVRAPLDWALPLSEVPSDWEVDDLLCSLLSP
  PASLNILSSSNPCLVHHDHTYSLPRETVSMDLESESCRKEGTQMTPQHMEELAEQEIARL
  VLTDEEKSLLEKEGLILPETLPLTKTEEQILKRVRRKIRNKRSAQESRRKKKVYVGGLES
  RVLKYTAQNMELQNKVQLLEEQNLSLLDQLRKLQAMVIEISNKTSSSSTCILVLLVSFCL
  LLVPAMYSSDTRGSLPAEHGVLSRQLRALPSEDPYQLELPALQSEVPKDSTHQWLDGSDC
  VLQAPGNTSCLLHYMPQAPSAEPPLEWPFPDLFSEPLCRGPILPLQANLTRKGGWLPTGS
  PSVILQDRYSG
• Function: Endoplasmic reticulum (ER)-bound sequence-specific transcription factor that directly binds DNA and activates transcription. Plays a role in the unfolded protein response (UPR), promoting cell survival versus ER stress-induced apoptotic cell death. Also involved in cell proliferation, migration and differentiation, tumor suppression and inflammatory gene expression. Acts as a positive regulator of LKN-1/CCL15-induced chemotaxis signaling of leukocyte cell migration. Associates with chromatin to the HERPUD1 promoter. Also induces transcriptional activation of chemokine receptors ; (Microbial infection) Plays a role in human immunodeficiency virus type 1 (HIV-1) virus protein expression; [Isoform 1]: (Microbial infection) May play a role as a cellular tumor suppressor that is targeted by the hepatitis C virus (HCV) core protein; [Isoform 1]: (Microbial infection) Plays a role in herpes simplex virus-1 (HSV-1) latent infection and reactivation from latency. Represses the VP16-mediated transactivation of immediate early genes of the HSV-1 virus by sequestering host cell factor-1 HCFC1 in the ER membrane of sensory neurons, thereby preventing the initiation of the replicative cascade leading to latent infection; [Isoform 2]: Functions as a negative transcriptional regulator in ligand-induced transcriptional activation of the glucocorticoid receptor NR3C1 by recruiting and activating histone deacetylases (HDAC1, HDAC2 and HDAC6). Also decreases the acetylation level of histone H4. Does not promote the chemotactic activity of leukocyte cells; [Processed cyclic AMP-responsive element-binding protein 3]: This is the transcriptionally active form that translocates to the nucleus and activates unfolded protein response (UPR) target genes during endoplasmic reticulum (ER) stress response. Binds the cAMP response element (CRE) (consensus: 5'-GTGACGT[AG][AG]-3') and C/EBP sequences present in many promoters to activate transcription of the genes. Binds to the unfolded protein response element (UPRE) consensus sequences sites. Binds DNA to the 5'-CCAC[GA]-3'half of ERSE II (5'-ATTGG-N-CCACG-3'); [Processed cyclic AMP-responsive element-binding protein 3]: (Microbial infection) Activates transcription of genes required for reactivation of the latent HSV-1 virus. It's transcriptional activity is inhibited by CREBZF in a HCFC1-dependent manner, by the viral transactivator protein VP16. Binds DNA to the cAMP response element (CRE) (consensus: 5'-GTGACGT[AG][AG]-3') and C/EBP sequences present in many viral promoters; [Processed cyclic AMP-responsive element-binding protein 3]: (Microbial infection) It's transcriptional activity is inhibited by CREBZF in a HCFC1-dependent manner, by the viral transactivator HCV core protein.
• Tissue Specificity: Ubiquitously expressed . Expressed in dendritic cells (DC). Weakly expressed in monocytes (at protein level) .
• KEGG Pathway:
  cGMP-PKG sig.ling pathway (hsa04022)
  cAMP sig.ling pathway (hsa04024)
  PI3K-Akt sig.ling pathway (hsa04151)
  AMPK sig.ling pathway (hsa04152)
  Longevity regulating pathway (hsa04211)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  TNF sig.ling pathway (hsa04668)
  Thermogenesis (hsa04714)
  Cholinergic sy.pse (hsa04725)
  Dopaminergic sy.pse (hsa04728)
  Insulin secretion (hsa04911)
  Estrogen sig.ling pathway (hsa04915)
  Melanogenesis (hsa04916)
  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)
  Insulin resistance (hsa04931)
  Cushing syndrome (hsa04934)
  Growth hormone synthesis, secretion and action (hsa04935)
  Vasopressin-regulated water reabsorption (hsa04962)
  Huntington disease (hsa05016)
  Prion disease (hsa05020)
  Cocaine addiction (hsa05030)
  Amphetamine addiction (hsa05031)
  Alcoholism (hsa05034)
  Hepatitis B (hsa05161)
  Human cytomegalovirus infection (hsa05163)
  Human papillomavirus infection (hsa05165)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Viral carcinogenesis (hsa05203)
  Chemical carcinogenesis - receptor activation (hsa05207)
  Prostate cancer (hsa05215)
• Reactome Pathway: CREB3 factors activate genes (R-HSA-8874211)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Definitive	Biomarker	[1]
Glioblastoma multiforme	DISK8246	Definitive	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[3]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[3]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[4]
Epithelial ovarian cancer	DIS56MH2	Strong	Genetic Variation	[5]
Fatty liver disease	DIS485QZ	Strong	Altered Expression	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[7]
Metabolic disorder	DIS71G5H	Strong	Altered Expression	[8]
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[4]
Ovarian cancer	DISZJHAP	Strong	Genetic Variation	[5]
Ovarian neoplasm	DISEAFTY	Strong	Genetic Variation	[5]
Adrenocortical insufficiency	DISZ0CPT	moderate	Altered Expression	[9]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[4]
Hepatitis C virus infection	DISQ0M8R	Limited	Altered Expression	[10]
Prostate cancer	DISF190Y	Limited	Biomarker	[11]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[11]
Prostate neoplasm	DISHDKGQ	Limited	Altered Expression	[11]
Rheumatoid arthritis	DISTSB4J	Limited	Biomarker	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Cyclic AMP-responsive element-binding protein 3 (CREB3) affects the response to substance of Methotrexate.	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Cyclic AMP-responsive element-binding protein 3 (CREB3).	[13]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Cyclic AMP-responsive element-binding protein 3 (CREB3).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Cyclic AMP-responsive element-binding protein 3 (CREB3).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cyclic AMP-responsive element-binding protein 3 (CREB3).	[16]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Cyclic AMP-responsive element-binding protein 3 (CREB3).	[17]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Cyclic AMP-responsive element-binding protein 3 (CREB3).	[17]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Cyclic AMP-responsive element-binding protein 3 (CREB3).	[18]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Cyclic AMP-responsive element-binding protein 3 (CREB3).	[19]
Selenium	DM25CGV	Approved	Selenium increases the expression of Cyclic AMP-responsive element-binding protein 3 (CREB3).	[20]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Cyclic AMP-responsive element-binding protein 3 (CREB3).	[15]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Cyclic AMP-responsive element-binding protein 3 (CREB3).	[20]
geraniol	DMS3CBD	Investigative	geraniol increases the expression of Cyclic AMP-responsive element-binding protein 3 (CREB3).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Cyclic AMP-responsive element-binding protein 3 (CREB3).	[21]

References

• [1] Knockdown of CREB3 activates endoplasmic reticulum stress and induces apoptosis in glioblastoma.Aging (Albany NY). 2019 Oct 13;11(19):8156-8168. doi: 10.18632/aging.102310. Epub 2019 Oct 13.
• [2] PAR-4 is involved in regulation of beta-secretase cleavage of the Alzheimer amyloid precursor protein.J Biol Chem. 2005 Apr 8;280(14):13824-32. doi: 10.1074/jbc.M411933200. Epub 2005 Jan 25.
• [3] Human sLZIP promotes atherosclerosis via MMP-9 transcription and vascular smooth muscle cell migration.FASEB J. 2014 Nov;28(11):5010-21. doi: 10.1096/fj.14-259218. Epub 2014 Jul 30.
• [4] Circular RNA circTADA2A promotes osteosarcoma progression and metastasis by sponging miR-203a-3p and regulating CREB3 expression.Mol Cancer. 2019 Apr 2;18(1):73. doi: 10.1186/s12943-019-1007-1.
• [5] High-throughput assessment of the antibody profile in ovarian cancer ascitic fluids.Oncoimmunology. 2019 Jun 4;8(9):e1614856. doi: 10.1080/2162402X.2019.1614856. eCollection 2019.
• [6] Human leucine zipper protein promotes hepatic steatosis via induction of apolipoprotein A-IV.FASEB J. 2017 Jun;31(6):2548-2561. doi: 10.1096/fj.201601227R. Epub 2017 Feb 28.
• [7] Upregulation of Leucine Zipper Protein mRNA in Hepatocellular Carcinoma Associated With Poor Prognosis.Technol Cancer Res Treat. 2016 Jun;15(3):517-22. doi: 10.1177/1533034615587432. Epub 2015 Jun 1.
• [8] The Role of Mammalian Creb3-Like Transcription Factors in Response to Nutrients.Front Genet. 2019 Jun 21;10:591. doi: 10.3389/fgene.2019.00591. eCollection 2019.
• [9] Circadian Rhythm of Glucocorticoid Administration Entrains Clock Genes in Immune Cells: A DREAM Trial Ancillary Study.J Clin Endocrinol Metab. 2018 Aug 1;103(8):2998-3009. doi: 10.1210/jc.2018-00346.
• [10] The liver-enriched transcription factor CREB-H is a growth suppressor protein underexpressed in hepatocellular carcinoma.Nucleic Acids Res. 2005 Mar 30;33(6):1859-73. doi: 10.1093/nar/gki332. Print 2005.
• [11] The role of sLZIP in cyclin D3-mediated negative regulation of androgen receptor transactivation and its involvement in prostate cancer.Oncogene. 2015 Jan 8;34(2):226-36. doi: 10.1038/onc.2013.538. Epub 2014 Jan 20.
• [12] Suppression of vascular permeability and inflammation by targeting of the transcription factor c-Jun.Nat Biotechnol. 2006 Jul;24(7):856-63. doi: 10.1038/nbt1225. Epub 2006 Jul 2.
• [13] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [14] 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.
• [15] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [16] 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.
• [17] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [18] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [19] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [20] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [21] Bisphenol-A impairs cellular function and alters DNA methylation of stress pathway genes in first trimester trophoblast cells. Reprod Toxicol. 2018 Dec;82:72-79.
• [22] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.
• [23] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.