Details of Drug Off-Target (DOT)

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

• DOT Name: Cardiotrophin-like cytokine factor 1 (CLCF1)
• Synonyms: B-cell-stimulating factor 3; BSF-3; Novel neurotrophin-1; NNT-1
• Gene Name: CLCF1
• Related Disease:
  Cold-induced sweating syndrome 2
  Cold-induced sweating syndrome
  Cold-induced sweating syndrome 1
• UniProt ID: CLCF1_HUMAN
• PDB ID: 8D7H; 8D7R
• Pfam ID: PF06875
• Sequence:
  MDLRAGDSWGMLACLCTVLWHLPAVPALNRTGDPGPGPSIQKTYDLTRYLEHQLRSLAGT
  YLNYLGPPFNEPDFNPPRLGAETLPRATVDLEVWRSLNDKLRLTQNYEAYSHLLCYLRGL
  NRQAATAELRRSLAHFCTSLQGLLGSIAGVMAALGYPLPQPLPGTEPTWTPGPAHSDFLQ
  KMDDFWLLKELQTWLWRSAKDFNRLKKKMQPPAAAVTLHLGAHGF
• Function: In complex with CRLF1, forms a heterodimeric neurotropic cytokine that plays a crucial role during neuronal development (Probable). Also stimulates B-cells. Binds to and activates the ILST/gp130 receptor.
• Tissue Specificity: Expressed predominantly in lymph nodes, spleen, peripheral blood lymphocytes, bone marrow, and fetal liver.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  JAK-STAT sig.ling pathway (hsa04630)
• Reactome Pathway: IL-6-type cytokine receptor ligand interactions (R-HSA-6788467)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cold-induced sweating syndrome 2	DISHHGUD	Strong	Autosomal recessive	[1]
Cold-induced sweating syndrome	DISSVMUD	Supportive	Autosomal recessive	[2]
Cold-induced sweating syndrome 1	DISMMSP9	Supportive	Autosomal recessive	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Cardiotrophin-like cytokine factor 1 (CLCF1).	[4]

18 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 Cardiotrophin-like cytokine factor 1 (CLCF1).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Cardiotrophin-like cytokine factor 1 (CLCF1).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Cardiotrophin-like cytokine factor 1 (CLCF1).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Cardiotrophin-like cytokine factor 1 (CLCF1).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Cardiotrophin-like cytokine factor 1 (CLCF1).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Cardiotrophin-like cytokine factor 1 (CLCF1).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Cardiotrophin-like cytokine factor 1 (CLCF1).	[11]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Cardiotrophin-like cytokine factor 1 (CLCF1).	[12]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Cardiotrophin-like cytokine factor 1 (CLCF1).	[13]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Cardiotrophin-like cytokine factor 1 (CLCF1).	[14]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Cardiotrophin-like cytokine factor 1 (CLCF1).	[15]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Cardiotrophin-like cytokine factor 1 (CLCF1).	[16]
Cetrorelix	DMFD9Q6	Approved	Cetrorelix decreases the expression of Cardiotrophin-like cytokine factor 1 (CLCF1).	[17]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Cardiotrophin-like cytokine factor 1 (CLCF1).	[18]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Cardiotrophin-like cytokine factor 1 (CLCF1).	[19]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Cardiotrophin-like cytokine factor 1 (CLCF1).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Cardiotrophin-like cytokine factor 1 (CLCF1).	[21]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Cardiotrophin-like cytokine factor 1 (CLCF1).	[22]

References

• [1] Inactivation of cardiotrophin-like cytokine, a second ligand for ciliary neurotrophic factor receptor, leads to cold-induced sweating syndrome in a patient. Proc Natl Acad Sci U S A. 2006 Jun 27;103(26):10068-73. doi: 10.1073/pnas.0509598103. Epub 2006 Jun 16.
• [2] Use of azathioprine in nine children with Crohn's disease. Va Med Q. 1991 Summer;118(3):169-70.
• [3] Cold-induced sweating syndrome: CISS1 and CISS2: manifestations from infancy to adulthood. Four new cases. J Neurol Sci. 2010 Jun 15;293(1-2):68-75. doi: 10.1016/j.jns.2010.02.028. Epub 2010 Apr 18.
• [4] 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.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [9] 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.
• [10] 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.
• [11] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [12] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [13] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [14] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [15] 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.
• [16] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [17] Luteinizing Hormone-Releasing Hormone (LHRH)-I antagonist cetrorelix inhibits myeloma cell growth in vitro and in vivo. Mol Cancer Ther. 2011 Jan;10(1):148-58. doi: 10.1158/1535-7163.MCT-10-0829. Epub 2010 Nov 9.
• [18] Grape resveratrol increases serum adiponectin and downregulates inflammatory genes in peripheral blood mononuclear cells: a triple-blind, placebo-controlled, one-year clinical trial in patients with stable coronary artery disease. Cardiovasc Drugs Ther. 2013 Feb;27(1):37-48. doi: 10.1007/s10557-012-6427-8.
• [19] Synergistic effect of JQ1 and rapamycin for treatment of human osteosarcoma. Int J Cancer. 2015 May 1;136(9):2055-64.
• [20] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [21] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [22] Persistence of epigenomic effects after recovery from repeated treatment with two nephrocarcinogens. Front Genet. 2018 Dec 3;9:558.