Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT55PXIN)

• DOT Name: Cytokine receptor-like factor 1 (CRLF1)
• Synonyms: Cytokine-like factor 1; CLF-1; ZcytoR5
• Gene Name: CRLF1
• Related Disease:
  Cold-induced sweating syndrome 1
  Cold-induced sweating syndrome
  Idiopathic achalasia
• UniProt ID: CRLF1_HUMAN
• PDB ID: 8D7H
• Pfam ID: PF09067 ; PF00041
• Sequence:
  MPAGRRGPAAQSARRPPPLLPLLLLLCVLGAPRAGSGAHTAVISPQDPTLLIGSSLLATC
  SVHGDPPGATAEGLYWTLNGRRLPPELSRVLNASTLALALANLNGSRQRSGDNLVCHARD
  GSILAGSCLYVGLPPEKPVNISCWSKNMKDLTCRWTPGAHGETFLHTNYSLKYKLRWYGQ
  DNTCEEYHTVGPHSCHIPKDLALFTPYEIWVEATNRLGSARSDVLTLDILDVVTTDPPPD
  VHVSRVGGLEDQLSVRWVSPPALKDFLFQAKYQIRYRVEDSVDWKVVDDVSNQTSCRLAG
  LKPGTVYFVQVRCNPFGIYGSKKAGIWSEWSHPTAASTPRSERPGPGGGACEPRGGEPSS
  GPVRRELKQFLGWLKKHAYCSNLSFRLYDQWRAWMQKSHKTRNQDEGILPSGRRGTARGP
  AR
• Function: In complex with CLCF1, forms a heterodimeric neurotropic cytokine that plays a crucial role during neuronal development (Probable). May also play a regulatory role in the immune system.
• Tissue Specificity: Highest levels of expression observed in spleen, thymus, lymph node, appendix, bone marrow, stomach, placenta, heart, thyroid and ovary. Strongly expressed also in fetal lung.
• Reactome Pathway:
  Interleukin-27 signaling (R-HSA-9020956)
  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 1	DISMMSP9	Definitive	Autosomal recessive	[1]
Cold-induced sweating syndrome	DISSVMUD	Supportive	Autosomal recessive	[2]
Idiopathic achalasia	DISBZNRO	Supportive	Autosomal recessive	[3]

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 Cytokine receptor-like factor 1 (CRLF1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Cytokine receptor-like factor 1 (CRLF1).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Cytokine receptor-like factor 1 (CRLF1).	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Cytokine receptor-like factor 1 (CRLF1).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Cytokine receptor-like factor 1 (CRLF1).	[8]
Marinol	DM70IK5	Approved	Marinol increases the expression of Cytokine receptor-like factor 1 (CRLF1).	[9]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Cytokine receptor-like factor 1 (CRLF1).	[10]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Cytokine receptor-like factor 1 (CRLF1).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Cytokine receptor-like factor 1 (CRLF1).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Cytokine receptor-like factor 1 (CRLF1).	[14]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Cytokine receptor-like factor 1 (CRLF1).	[15]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Cytokine receptor-like factor 1 (CRLF1).	[16]

1 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 Cytokine receptor-like factor 1 (CRLF1).	[13]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] Cold-Induced Sweating Syndrome Including Crisponi Syndrome. 2011 Mar 3 [updated 2021 Aug 12]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [3] Mutations in CRLF1 cause familial achalasia. Clin Genet. 2017 Jul;92(1):104-108. doi: 10.1111/cge.12953. Epub 2017 Mar 15.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] 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.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] 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.
• [8] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [9] 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.
• [10] Progesterone regulation of implantation-related genes: new insights into the role of oestrogen. Cell Mol Life Sci. 2007 Apr;64(7-8):1009-32.
• [11] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [12] 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.
• [13] 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.
• [14] Cultured human peripheral blood mononuclear cells alter their gene expression when challenged with endocrine-disrupting chemicals. Toxicology. 2013 Jan 7;303:17-24.
• [15] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [16] Linking site-specific loss of histone acetylation to repression of gene expression by the mycotoxin ochratoxin A. Arch Toxicol. 2018 Feb;92(2):995-1014.