Details of Drug Off-Target (DOT)

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

• DOT Name: Complement C1r subcomponent-like protein (C1RL)
• Synonyms: C1r-LP; C1r-like protein; EC 3.4.21.-; C1r-like serine protease analog protein; CLSPa
• Gene Name: C1RL
• Related Disease:
  B-cell lymphoma
  Non-hodgkin lymphoma
  Systemic lupus erythematosus
• UniProt ID: C1RL_HUMAN
• EC Number: 3.4.21.-
• Pfam ID: PF00431 ; PF00089
• Sequence:
  MPGPRVWGKYLWRSPHSKGCPGAMWWLLLWGVLQACPTRGSVLLAQELPQQLTSPGYPEP
  YGKGQESSTDIKAPEGFAVRLVFQDFDLEPSQDCAGDSVTISFVGSDPSQFCGQQGSPLG
  RPPGQREFVSSGRSLRLTFRTQPSSENKTAHLHKGFLALYQTVAVNYSQPISEASRGSEA
  INAPGDNPAKVQNHCQEPYYQAAAAGALTCATPGTWKDRQDGEEVLQCMPVCGRPVTPIA
  QNQTTLGSSRAKLGNFPWQAFTSIHGRGGGALLGDRWILTAAHTIYPKDSVSLRKNQSVN
  VFLGHTAIDEMLKLGNHPVHRVVVHPDYRQNESHNFSGDIALLELQHSIPLGPNVLPVCL
  PDNETLYRSGLLGYVSGFGMEMGWLTTELKYSRLPVAPREACNAWLQKRQRPEVFSDNMF
  CVGDETQRHSVCQGDSGSVYVVWDNHAHHWVATGIVSWGIGCGEGYDFYTKVLSYVDWIK
  GVMNGKN
• Function: Mediates the proteolytic cleavage of HP/haptoglobin in the endoplasmic reticulum.
• Tissue Specificity: Highly expressed in placenta, liver, kidney, pancreas, moderately in lung, spleen, prostate, ovary, colon, and PBL, and weakly in heart, skeletal muscle, thymus, testis, and small intestine. Expressed in PC-3 (prostate adenocarcinoma) and SK-OV-3 (ovary adenocarcinoma) cells, but not in LoVo and HT-29 (colon adenocarcinoma), SMMC7721 (hepatocellular carcinoma), CaoV-3 (ovary adenocarcinoma), HeLa (cervix epithelioid carcinoma), MCF-7 (breast adenocarcinoma), U-251MG (glioma) or A-549 (lung carcinoma) cells. Widely expressed in myeloid leukemia cell lines, including K-562 (chronic myelogenous leukemia), THP-1 (myelomonocytic leukemia), HL-60 and NB4 (promyelocytic leukemia), and KG-1 (acute myelogenous leukemia) cells. Expressed mainly in the liver and in serum (at protein level).

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
B-cell lymphoma	DISIH1YQ	Strong	Genetic Variation	[1]
Non-hodgkin lymphoma	DISS2Y8A	Strong	Genetic Variation	[1]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Complement C1r subcomponent-like protein (C1RL).	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Complement C1r subcomponent-like protein (C1RL).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Complement C1r subcomponent-like protein (C1RL).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Complement C1r subcomponent-like protein (C1RL).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Complement C1r subcomponent-like protein (C1RL).	[7]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Complement C1r subcomponent-like protein (C1RL).	[8]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Complement C1r subcomponent-like protein (C1RL).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Complement C1r subcomponent-like protein (C1RL).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Complement C1r subcomponent-like protein (C1RL).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Complement C1r subcomponent-like protein (C1RL).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Complement C1r subcomponent-like protein (C1RL).	[13]

References

• [1] Polymorphisms in complement system genes and risk of non-Hodgkin lymphoma.Environ Mol Mutagen. 2012 Mar;53(2):145-51. doi: 10.1002/em.21675. Epub 2011 Dec 15.
• [2] Investigation of C1-complex regions reveals new C1Q variants associated with protection from systemic lupus erythematosus, and affect its transcript abundance.Sci Rep. 2018 May 23;8(1):8048. doi: 10.1038/s41598-018-26380-x.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [9] 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.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [12] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [13] 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.