Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT09MHV0)

• DOT Name: Cyclic AMP-responsive element-binding protein 3-like protein 2 (CREB3L2)
• Synonyms: cAMP-responsive element-binding protein 3-like protein 2; BBF2 human homolog on chromosome 7
• Gene Name: CREB3L2
• Related Disease:
  Advanced cancer
  Carcinoma
  Fibrosarcoma
  Sarcoma
  Soft tissue neoplasm
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid tumor
  Adult glioblastoma
  Glioblastoma multiforme
  Malignant glioma
  Neoplasm
  Soft tissue sarcoma
• UniProt ID: CR3L2_HUMAN
• Pfam ID: PF00170
• Sequence:
  MEVLESGEQGVLQWDRKLSELSEPGDGEALMYHTHFSELLDEFSQNVLGQLLNDPFLSEK
  SVSMEVEPSPTSPAPLIQAEHSYSLCEEPRAQSPFTHITTSDSFNDDEVESEKWYLSTDF
  PSTSIKTEPVTDEPPPGLVPSVTLTITAISTPLEKEEPPLEMNTGVDSSCQTIIPKIKLE
  PHEVDQFLNFSPKEAPVDHLHLPPTPPSSHGSDSEGSLSPNPRLHPFSLPQTHSPSRAAP
  RAPSALSSSPLLTAPHKLQGSGPLVLTEEEKRTLIAEGYPIPTKLPLSKSEEKALKKIRR
  KIKNKISAQESRRKKKEYMDSLEKKVESCSTENLELRKKVEVLENTNRTLLQQLQKLQTL
  VMGKVSRTCKLAGTQTGTCLMVVVLCFAVAFGSFFQGYGPYPSATKMALPSQHSLQEPYT
  ASVVRSRNLLIYEEHSPPEESSSPGSAGELGGWDRGSSLLRVSGLESRPDVDLPHFIISN
  ETSLEKSVLLELQQHLVSAKLEGNETLKVVELDRRVNTTF
• Function: Transcription factor involved in unfolded protein response (UPR). In the absence of endoplasmic reticulum (ER) stress, inserted into ER membranes, with N-terminal DNA-binding and transcription activation domains oriented toward the cytosolic face of the membrane. In response to ER stress, transported to the Golgi, where it is cleaved in a site-specific manner by resident proteases S1P/MBTPS1 and S2P/MBTPS2. The released N-terminal cytosolic domain is translocated to the nucleus to effect transcription of specific target genes. Plays a critical role in chondrogenesis by activating the transcription of SEC23A, which promotes the transport and secretion of cartilage matrix proteins, and possibly that of ER biogenesis-related genes. In a neuroblastoma cell line, protects cells from ER stress-induced death. In vitro activates transcription of target genes via direct binding to the CRE site.
• Tissue Specificity: Widely expressed with highest levels in placenta, lung, spleen and intestine, and lowest levels in heart, brain, skeletal muscle, thymus, colon and leukocytes. In fetal tissues, the weakest expression is detected in brain and heart.
• 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

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Carcinoma	DISH9F1N	Strong	Biomarker	[2]
Fibrosarcoma	DISWX7MU	Strong	Biomarker	[3]
Sarcoma	DISZDG3U	Strong	Genetic Variation	[4]
Soft tissue neoplasm	DISP2OHE	Strong	Biomarker	[5]
Thyroid cancer	DIS3VLDH	Strong	Genetic Variation	[2]
Thyroid gland carcinoma	DISMNGZ0	Strong	Genetic Variation	[2]
Thyroid tumor	DISLVKMD	Strong	Genetic Variation	[2]
Adult glioblastoma	DISVP4LU	moderate	Altered Expression	[1]
Glioblastoma multiforme	DISK8246	moderate	Altered Expression	[1]
Malignant glioma	DISFXKOV	moderate	Altered Expression	[6]
Neoplasm	DISZKGEW	moderate	Altered Expression	[1]
Soft tissue sarcoma	DISSN8XB	moderate	Genetic Variation	[4]

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-like protein 2 (CREB3L2).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Cyclic AMP-responsive element-binding protein 3-like protein 2 (CREB3L2).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Cyclic AMP-responsive element-binding protein 3-like protein 2 (CREB3L2).	[9]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Cyclic AMP-responsive element-binding protein 3-like protein 2 (CREB3L2).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Cyclic AMP-responsive element-binding protein 3-like protein 2 (CREB3L2).	[11]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Cyclic AMP-responsive element-binding protein 3-like protein 2 (CREB3L2).	[12]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Cyclic AMP-responsive element-binding protein 3-like protein 2 (CREB3L2).	[13]
AMEP	DMFELMQ	Phase 1	AMEP increases the expression of Cyclic AMP-responsive element-binding protein 3-like protein 2 (CREB3L2).	[16]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Cyclic AMP-responsive element-binding protein 3-like protein 2 (CREB3L2).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Cyclic AMP-responsive element-binding protein 3-like protein 2 (CREB3L2).	[19]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Cyclic AMP-responsive element-binding protein 3-like protein 2 (CREB3L2).	[16]
geraniol	DMS3CBD	Investigative	geraniol increases the expression of Cyclic AMP-responsive element-binding protein 3-like protein 2 (CREB3L2).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Cyclic AMP-responsive element-binding protein 3-like protein 2 (CREB3L2).	[14]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Cyclic AMP-responsive element-binding protein 3-like protein 2 (CREB3L2).	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Cyclic AMP-responsive element-binding protein 3-like protein 2 (CREB3L2).	[17]

References

• [1] Promotion of Cancer Cell Proliferation by Cleaved and Secreted Luminal Domains of ER Stress Transducer BBF2H7.PLoS One. 2015 May 8;10(5):e0125982. doi: 10.1371/journal.pone.0125982. eCollection 2015.
• [2] CREB3L2-PPARgamma fusion mutation identifies a thyroid signaling pathway regulated by intramembrane proteolysis.Cancer Res. 2008 Sep 1;68(17):7156-64. doi: 10.1158/0008-5472.CAN-08-1085.
• [3] Translocation-positive low-grade fibromyxoid sarcoma: clinicopathologic and molecular analysis of a series expanding the morphologic spectrum and suggesting potential relationship to sclerosing epithelioid fibrosarcoma: a study from the French Sarcoma Group.Am J Surg Pathol. 2007 Sep;31(9):1387-402. doi: 10.1097/PAS.0b013e3180321959.
• [4] Low-grade fibromyxoid sarcoma with prominent giant rosettes and heterotopic ossification.Pathol Res Pract. 2012 Sep 15;208(9):557-60. doi: 10.1016/j.prp.2012.06.002. Epub 2012 Jul 20.
• [5] Molecular detection of FUS-CREB3L2 fusion transcripts in low-grade fibromyxoid sarcoma using formalin-fixed, paraffin-embedded tissue specimens.Am J Surg Pathol. 2006 Sep;30(9):1077-84. doi: 10.1097/01.pas.0000209830.24230.1f.
• [6] A genome-wide RNA interference screen reveals an essential CREB3L2-ATF5-MCL1 survival pathway in malignant glioma with therapeutic implications.Nat Med. 2010 Jun;16(6):671-7. doi: 10.1038/nm.2158. Epub 2010 May 23.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [9] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [10] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [11] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [12] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [13] 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.
• [14] 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.
• [15] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [16] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.
• [17] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [18] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [19] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [20] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.