Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSGQGT2)

• DOT Name: Cyclic AMP-responsive element-binding protein 3-like protein 4 (CREB3L4)
• Synonyms: cAMP-responsive element-binding protein 3-like protein 4; Androgen-induced basic leucine zipper protein; AIbZIP; Attaching to CRE-like 1; ATCE1; Cyclic AMP-responsive element-binding protein 4; CREB-4; cAMP-responsive element-binding protein 4; Transcript induced in spermiogenesis protein 40; Tisp40; hJAL
• Gene Name: CREB3L4
• Related Disease:
  Adenocarcinoma
  Epithelial ovarian cancer
  Kidney cancer
  Neuralgia
  Obesity
  Ovarian cancer
  Ovarian neoplasm
  Prostate carcinoma
  Renal carcinoma
  Renal fibrosis
  Breast cancer
  Breast carcinoma
  Neoplasm
  Prostate cancer
  Prostate neoplasm
• UniProt ID: CR3L4_HUMAN
• Pfam ID: PF00170
• Sequence:
  MDLGIPDLLDAWLEPPEDIFSTGSVLELGLHCPPPEVPVTRLQEQGLQGWKSGGDRGCGL
  QESEPEDFLKLFIDPNEVYCSEASPGSDSGISEDPCHPDSPPAPRATSSPMLYEVVYEAG
  ALERMQGETGPNVGLISIQLDQWSPAFMVPDSCMVSELPFDAHAHILPRAGTVAPVPCTT
  LLPCQTLFLTDEEKRLLGQEGVSLPSHLPLTKAEERVLKKVRRKIRNKQSAQDSRRRKKE
  YIDGLESRVAACSAQNQELQKKVQELERHNISLVAQLRQLQTLIAQTSNKAAQTSTCVLI
  LLFSLALIILPSFSPFQSRPEAGSEDYQPHGVTSRNILTHKDVTENLETQVVESRLREPP
  GAKDANGSTRTLLEKMGGKPRPSGRIRSVLHADEM
• Function: Transcriptional activator that may play a role in the unfolded protein response. Binds to the UPR element (UPRE) but not to CRE element. Preferentially binds DNA with to the consensus sequence 5'-T[GT]ACGT[GA][GT]-3' and has transcriptional activation activity from UPRE. Binds to NF-kappa-B site and has transcriptional activation activity from NF-kappa-B-containing regulatory elements.
• Tissue Specificity: According to PubMed:11830526, exclusively expressed in the prostate. Expressed in breast and prostate cancer cell lines. Expressed in prostatic luminal epithelial cells (at protein level). Expression is significantly more abundant in prostate cancer than in benign prostatic tissue (prostatic hyperplasia). According to PubMed:12111373, also expressed in brain, pancreas and skeletal muscle, and at lower levels in small intestine, testis, leukocyte and thymus.
• 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

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Definitive	Biomarker	[1]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[2]
Kidney cancer	DISBIPKM	Strong	Altered Expression	[3]
Neuralgia	DISWO58J	Strong	Biomarker	[4]
Obesity	DIS47Y1K	Strong	Altered Expression	[5]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[2]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[2]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[6]
Renal carcinoma	DISER9XT	Strong	Altered Expression	[3]
Renal fibrosis	DISMHI3I	Strong	Altered Expression	[7]
Breast cancer	DIS7DPX1	Limited	Biomarker	[8]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[8]
Neoplasm	DISZKGEW	Limited	Altered Expression	[3]
Prostate cancer	DISF190Y	Limited	Biomarker	[6]
Prostate neoplasm	DISHDKGQ	Limited	Biomarker	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Cyclic AMP-responsive element-binding protein 3-like protein 4 (CREB3L4).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Cyclic AMP-responsive element-binding protein 3-like protein 4 (CREB3L4).	[11]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Cyclic AMP-responsive element-binding protein 3-like protein 4 (CREB3L4).	[12]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Cyclic AMP-responsive element-binding protein 3-like protein 4 (CREB3L4).	[13]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Cyclic AMP-responsive element-binding protein 3-like protein 4 (CREB3L4).	[14]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Cyclic AMP-responsive element-binding protein 3-like protein 4 (CREB3L4).	[14]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Cyclic AMP-responsive element-binding protein 3-like protein 4 (CREB3L4).	[15]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Cyclic AMP-responsive element-binding protein 3-like protein 4 (CREB3L4).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Cyclic AMP-responsive element-binding protein 3-like protein 4 (CREB3L4).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Cyclic AMP-responsive element-binding protein 3-like protein 4 (CREB3L4).	[18]
CH-223191	DMMJZYC	Investigative	CH-223191 decreases the expression of Cyclic AMP-responsive element-binding protein 3-like protein 4 (CREB3L4).	[19]

References

• [1] MicroRNA-181b targets cAMP responsive element binding protein 1 in gastric adenocarcinomas.IUBMB Life. 2012 Jul;64(7):628-35. doi: 10.1002/iub.1030. Epub 2012 Apr 27.
• [2] Long noncoding RNA DQ786243 interacts with miR-506 and promotes progression of ovarian cancer through targeting cAMP responsive element binding protein 1.J Cell Biochem. 2018 Dec;119(12):9764-9780. doi: 10.1002/jcb.27295. Epub 2018 Aug 13.
• [3] Oncogenic cAMP responsive element binding protein 1 is overexpressed upon loss of tumor suppressive miR-10b-5p and miR-363-3p in renal cancer.Oncol Rep. 2016 Apr;35(4):1967-78. doi: 10.3892/or.2016.4579. Epub 2016 Jan 20.
• [4] Modulating cAMP responsive element binding protein 1 attenuates functional and behavioural deficits in rat model of neuropathic pain.Eur Rev Med Pharmacol Sci. 2019 Mar;23(6):2602-2611. doi: 10.26355/eurrev_201903_17410.
• [5] Genome-wide analysis identifies colonic genes differentially associated with serum leptin and insulin concentrations in C57BL/6J mice fed a high-fat diet.PLoS One. 2017 Feb 7;12(2):e0171664. doi: 10.1371/journal.pone.0171664. eCollection 2017.
• [6] The role of CREB3L4 in the proliferation of prostate cancer cells.Sci Rep. 2017 Mar 24;7:45300. doi: 10.1038/srep45300.
• [7] Identification of Tisp40 as an Essential Regulator of Renal Tubulointerstitial Fibrosis via TGF-/Smads Pathway.Cell Physiol Biochem. 2017;42(2):697-712. doi: 10.1159/000477887. Epub 2017 Jun 15.
• [8] Overexpression of MUC1 predicts poor prognosis in patients with breast cancer.Oncol Rep. 2019 Feb;41(2):801-810. doi: 10.3892/or.2018.6887. Epub 2018 Nov 27.
• [9] DNA methylome changes by estradiol benzoate and bisphenol A links early-life environmental exposures to prostate cancer risk.Epigenetics. 2016 Sep;11(9):674-689. doi: 10.1080/15592294.2016.1208891. Epub 2016 Jul 14.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [13] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [14] 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.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [17] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [18] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [19] Adaptive changes in global gene expression profile of lung carcinoma A549 cells acutely exposed to distinct types of AhR ligands. Toxicol Lett. 2018 Aug;292:162-174.