Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKEY2NJ)

• DOT Name: Cartilage intermediate layer protein 1 (CILP)
• Synonyms: CILP-1; Cartilage intermediate-layer protein
• Gene Name: CILP
• Related Disease:
  Type-1 diabetes
  Aortic valve stenosis
  Autoimmune disease
  Intervertebral disc degeneration
  Lhermitte-Duclos disease
  Narcolepsy
  Osteoarthritis
  Rheumatoid arthritis
• UniProt ID: CILP1_HUMAN
• Pfam ID: PF13927 ; PF13330 ; PF00090
• Sequence:
  MVGTKAWVFSFLVLEVTSVLGRQTMLTQSVRRVQPGKKNPSIFAKPADTLESPGEWTTWF
  NIDYPGGKGDYERLDAIRFYYGDRVCARPLRLEARTTDWTPAGSTGQVVHGSPREGFWCL
  NREQRPGQNCSNYTVRFLCPPGSLRRDTERIWSPWSPWSKCSAACGQTGVQTRTRICLAE
  MVSLCSEASEEGQHCMGQDCTACDLTCPMGQVNADCDACMCQDFMLHGAVSLPGGAPASG
  AAIYLLTKTPKLLTQTDSDGRFRIPGLCPDGKSILKITKVKFAPIVLTMPKTSLKAATIK
  AEFVRAETPYMVMNPETKARRAGQSVSLCCKATGKPRPDKYFWYHNDTLLDPSLYKHESK
  LVLRKLQQHQAGEYFCKAQSDAGAVKSKVAQLIVIASDETPCNPVPESYLIRLPHDCFQN
  ATNSFYYDVGRCPVKTCAGQQDNGIRCRDAVQNCCGISKTEEREIQCSGYTLPTKVAKEC
  SCQRCTETRSIVRGRVSAADNGEPMRFGHVYMGNSRVSMTGYKGTFTLHVPQDTERLVLT
  FVDRLQKFVNTTKVLPFNKKGSAVFHEIKMLRRKKPITLEAMETNIIPLGEVVGEDPMAE
  LEIPSRSFYRQNGEPYIGKVKASVTFLDPRNISTATAAQTDLNFINDEGDTFPLRTYGMF
  SVDFRDEVTSEPLNAGKVKVHLDSTQVKMPEHISTVKLWSLNPDTGLWEEEGDFKFENQR
  RNKREDRTFLVGNLEIRERRLFNLDVPESRRCFVKVRAYRSERFLPSEQIQGVVISVINL
  EPRTGFLSNPRAWGRFDSVITGPNGACVPAFCDDQSPDAYSAYVLASLAGEELQAVESSP
  KFNPNAIGVPQPYLNKLNYRRTDHEDPRVKKTAFQISMAKPRPNSAEESNGPIYAFENLR
  ACEEAPPSAAHFRFYQIEGDRYDYNTVPFNEDDPMSWTEDYLAWWPKPMEFRACYIKVKI
  VGPLEVNVRSRNMGGTHRQTVGKLYGIRDVRSTRDRDQPNVSAACLEFKCSGMLYDQDRV
  DRTLVKVIPQGSCRRASVNPMLHEYLVNHLPLAVNNDTSEYTMLAPLDPLGHNYGIYTVT
  DQDPRTAKEIALGRCFDGTSDGSSRIMKSNVGVALTFNCVERQVGRQSAFQYLQSTPAQS
  PAAGTVQGRVPSRRQQRASRGGQRQGGVVASLRFPRVAQQPLIN
• Function: Probably plays a role in cartilage scaffolding. May act by antagonizing TGF-beta1 (TGFB1) and IGF1 functions. Has the ability to suppress IGF1-induced proliferation and sulfated proteoglycan synthesis, and inhibits ligand-induced IGF1R autophosphorylation. May inhibit TGFB1-mediated induction of cartilage matrix genes via its interaction with TGFB1. Overexpression may lead to impair chondrocyte growth and matrix repair and indirectly promote inorganic pyrophosphate (PPi) supersaturation in aging and osteoarthritis cartilage.
• Tissue Specificity: Specifically expressed in cartilage. Localizes in the intermediates layer of articular cartilage but neither in the superficial nor in the deepest regions. Specifically and highly expressed in intervertebral disk tissue. Expression increases with aging in hip articular cartilage. Overexpressed in articular hyaline cartilage from patients with calcium pyrophosphate dihydrate crystal deposition disease (CPPD). Expression in intervertebral disk tissue from individuals with lumbar disk disease increases as disk degeneration progresses.
• Reactome Pathway: Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) (R-HSA-2404192)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Type-1 diabetes	DIS7HLUB	Definitive	Biomarker	[1]
Aortic valve stenosis	DISW7AQ9	Strong	Altered Expression	[2]
Autoimmune disease	DISORMTM	Strong	Biomarker	[3]
Intervertebral disc degeneration	DISG3AIM	Strong	Genetic Variation	[4]
Lhermitte-Duclos disease	DIS87XW7	Strong	Genetic Variation	[5]
Narcolepsy	DISLCNLI	Strong	Genetic Variation	[6]
Osteoarthritis	DIS05URM	Strong	Altered Expression	[7]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[3]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cartilage intermediate layer protein 1 (CILP) affects the response to substance of Cisplatin.	[15]

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 Cartilage intermediate layer protein 1 (CILP).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Cartilage intermediate layer protein 1 (CILP).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cartilage intermediate layer protein 1 (CILP).	[10]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Cartilage intermediate layer protein 1 (CILP).	[11]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Cartilage intermediate layer protein 1 (CILP).	[12]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Cartilage intermediate layer protein 1 (CILP).	[13]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Cartilage intermediate layer protein 1 (CILP).	[14]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Cartilage intermediate layer protein 1 (CILP).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Cartilage intermediate layer protein 1 (CILP).	[11]

References

• [1] Cartilage intermediate layer protein is regulated by mechanical stress and affects extracellular matrix synthesis.Mol Med Rep. 2018 Apr;17(4):6130-6137. doi: 10.3892/mmr.2018.8588. Epub 2018 Feb 12.
• [2] Cartilage intermediate layer protein 1 (CILP1): A novel mediator of cardiac extracellular matrix remodelling.Sci Rep. 2017 Nov 22;7(1):16042. doi: 10.1038/s41598-017-16201-y.
• [3] Proteomic surveillance of autoimmunity in osteoarthritis: identification of triosephosphate isomerase as an autoantigen in patients with osteoarthritis.Arthritis Rheum. 2004 May;50(5):1511-21. doi: 10.1002/art.20189.
• [4] Association Between Cartilage Intermediate Layer Protein and Degeneration of Intervertebral Disc: A Meta-analysis.Spine (Phila Pa 1976). 2016 Oct 15;41(20):E1244-E1248. doi: 10.1097/BRS.0000000000001749.
• [5] Association of CILP, COL9A2 and MMP3 Gene Polymorphisms with Lumbar Disc Degeneration in an Indian Population.J Mol Neurosci. 2018 Nov;66(3):378-382. doi: 10.1007/s12031-018-1182-3. Epub 2018 Oct 4.
• [6] Genome-wide association database developed in the Japanese Integrated Database Project.J Hum Genet. 2009 Sep;54(9):543-6. doi: 10.1038/jhg.2009.68. Epub 2009 Jul 24.
• [7] Analysis of Endogenous Peptides Released from Osteoarthritic Cartilage Unravels Novel Pathogenic Markers.Mol Cell Proteomics. 2019 Oct;18(10):2018-2028. doi: 10.1074/mcp.RA119.001554. Epub 2019 Jul 27.
• [8] 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.
• [9] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [10] 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.
• [11] 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.
• [12] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [13] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [14] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [15] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.