Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZK8PFX)

• DOT Name: RB1-inducible coiled-coil protein 1 (RB1CC1)
• Synonyms: FAK family kinase-interacting protein of 200 kDa; FIP200
• Gene Name: RB1CC1
• Related Disease:
  Advanced cancer
  Prostate cancer
  Prostate carcinoma
  Adult glioblastoma
  Astrocytoma
  Bone osteosarcoma
  Brain neoplasm
  Breast cancer
  Breast neoplasm
  Colonic neoplasm
  Colorectal carcinoma
  Colorectal neoplasm
  Diabetic kidney disease
  Dilated cardiomyopathy 1A
  Epithelial ovarian cancer
  Familial adenomatous polyposis
  Glioblastoma multiforme
  Invasive ductal breast carcinoma
  Metastatic malignant neoplasm
  Neoplasm
  Osteosarcoma
  Ovarian cancer
  Ovarian neoplasm
  Schizophrenia
  Breast carcinoma
  Chronic pancreatitis
  Retinoblastoma
• UniProt ID: RBCC1_HUMAN
• PDB ID: 6DCE; 6GMA; 7CZG; 7CZM; 7D0E; 7EA2; 7EAA; 8SOI; 8SQZ; 8SRM; 8SRQ
• Pfam ID: PF10377
• Sequence:
  MKLYVFLVNTGTTLTFDTELTVQTVADLKHAIQSKYKIAIQHQVLVVNGGECMAADRRVC
  TYSAGTDTNPIFLFNKEMILCDRPPAIPKTTFSTENDMEIKVEESLMMPAVFHTVASRTQ
  LALEMYEVAKKLCSFCEGLVHDEHLQHQGWAAIMANLEDCSNSYQKLLFKFESIYSNYLQ
  SIEDIKLKLTHLGTAVSVMAKIPLLECLTRHSYRECLGRLDSLPEHEDSEKAEMKRSTEL
  VLSPDMPRTTNESLLTSFPKSVEHVSPDTADAESGKEIRESCQSTVHQQDETTIDTKDGD
  LPFFNVSLLDWINVQDRPNDVESLVRKCFDSMSRLDPRIIRPFIAECRQTIAKLDNQNMK
  AIKGLEDRLYALDQMIASCGRLVNEQKELAQGFLANQKRAENLKDASVLPDLCLSHANQL
  MIMLQNHRKLLDIKQKCTTAKQELANNLHVRLKWCCFVMLHADQDGEKLQALLRLVIELL
  ERVKIVEALSTVPQMYCLAVVEVVRRKMFIKHYREWAGALVKDGKRLYEAEKSKRESFGK
  LFRKSFLRNRLFRGLDSWPPSFCTQKPRKFDCELPDISLKDLQFLQSFCPSEVQPFLRVP
  LLCDFEPLHQHVLALHNLVKAAQSLDEMSQTITDLLSEQKASVSQTSPQSASSPRMESTA
  GITTTTSPRTPPPLTVQDPLCPAVCPLEELSPDSIDAHTFDFETIPHPNIEQTIHQVSLD
  LDSLAESPESDFMSAVNEFVIEENLSSPNPISDPQSPEMMVESLYSSVINAIDSRRMQDT
  NVCGKEDFGDHTSLNVQLERCRVVAQDSHFSIQTIKEDLCHFRTFVQKEQCDFSNSLKCT
  AVEIRNIIEKVKCSLEITLKEKHQKELLSLKNEYEGKLDGLIKETEENENKIKKLKGELV
  CLEEVLQNKDNEFALVKHEKEAVICLQNEKDQKLLEMENIMHSQNCEIKELKQSREIVLE
  DLKKLHVENDEKLQLLRAELQSLEQSHLKELEDTLQVRHIQEFEKVMTDHRVSLEELKKE
  NQQIINQIQESHAEIIQEKEKQLQELKLKVSDLSDTRCKLEVELALKEAETDEIKILLEE
  SRAQQKETLKSLLEQETENLRTEISKLNQKIQDNNENYQVGLAELRTLMTIEKDQCISEL
  ISRHEEESNILKAELNKVTSLHNQAFEIEKNLKEQIIELQSKLDSELSALERQKDEKITQ
  QEEKYEAIIQNLEKDRQKLVSSQEQDREQLIQKLNCEKDEAIQTALKEFKLEREVVEKEL
  LEKVKHLENQIAKSPAIDSTRGDSSSLVAELQEKLQEEKAKFLEQLEEQEKRKNEEMQNV
  RTSLIAEQQTNFNTVLTREKMRKENIINDLSDKLKSTMQQQERDKDLIESLSEDRARLLE
  EKKKLEEEVSKLRSSSFVPSPYVATAPELYGACAPELPGESDRSAVETADEGRVDSAMET
  SMMSVQENIHMLSEEKQRIMLLERTLQLKEEENKRLNQRLMSQSMSSVSSRHSEKIAIRD
  FQVGDLVLIILDERHDNYVLFTVSPTLYFLHSESLPALDLKPGEGASGASRRPWVLGKVM
  EKEYCQAKKAQNRFKVPLGTKFYRVKAVSWNKKV
• Function: Involved in autophagy. Regulates early events but also late events of autophagosome formation through direct interaction with Atg16L1. Required for the formation of the autophagosome-like double-membrane structure that surrounds the Salmonella-containing vacuole (SCV) during S.typhimurium infection and subsequent xenophagy. Involved in repair of DNA damage caused by ionizing radiation, which subsequently improves cell survival by decreasing apoptosis. Inhibits PTK2/FAK1 and PTK2B/PYK2 kinase activity, affecting their downstream signaling pathways. Plays a role as a modulator of TGF-beta-signaling by restricting substrate specificity of RNF111. Functions as a DNA-binding transcription factor. Is a potent regulator of the RB1 pathway through induction of RB1 expression. Plays a crucial role in muscular differentiation. Plays an indispensable role in fetal hematopoiesis and in the regulation of neuronal homeostasis.
• Tissue Specificity: Expression levels correlated closely with those of RB1 in cancer cell lines as well as in various normal human tissues. Abundantly expressed in human musculoskeletal and cultured osteosarcoma cells.
• KEGG Pathway:
  Autophagy - animal (hsa04140)
  Longevity regulating pathway (hsa04211)
  Alzheimer disease (hsa05010)
  Amyotrophic lateral sclerosis (hsa05014)
  Huntington disease (hsa05016)
  Spinocerebellar ataxia (hsa05017)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
• Reactome Pathway: Macroautophagy (R-HSA-1632852)

Molecular Interaction Atlas (MIA) of This DOT

27 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Biomarker	[1]
Prostate cancer	DISF190Y	Definitive	Altered Expression	[2]
Prostate carcinoma	DISMJPLE	Definitive	Altered Expression	[2]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[3]
Astrocytoma	DISL3V18	Strong	Biomarker	[4]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[5]
Brain neoplasm	DISY3EKS	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[6]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[7]
Colonic neoplasm	DISSZ04P	Strong	Genetic Variation	[8]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[9]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[8]
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[10]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Altered Expression	[6]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[11]
Familial adenomatous polyposis	DISW53RE	Strong	Biomarker	[12]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[3]
Invasive ductal breast carcinoma	DIS43J58	Strong	Altered Expression	[6]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[13]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[5]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[11]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[11]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[14]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[6]
Chronic pancreatitis	DISBUOMJ	Limited	Biomarker	[15]
Retinoblastoma	DISVPNPB	Limited	Altered Expression	[15]

4 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 RB1-inducible coiled-coil protein 1 (RB1CC1).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of RB1-inducible coiled-coil protein 1 (RB1CC1).	[26]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of RB1-inducible coiled-coil protein 1 (RB1CC1).	[29]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the phosphorylation of RB1-inducible coiled-coil protein 1 (RB1CC1).	[33]

16 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 RB1-inducible coiled-coil protein 1 (RB1CC1).	[17]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of RB1-inducible coiled-coil protein 1 (RB1CC1).	[18]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of RB1-inducible coiled-coil protein 1 (RB1CC1).	[19]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of RB1-inducible coiled-coil protein 1 (RB1CC1).	[20]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of RB1-inducible coiled-coil protein 1 (RB1CC1).	[21]
Mifepristone	DMGZQEF	Approved	Mifepristone increases the expression of RB1-inducible coiled-coil protein 1 (RB1CC1).	[22]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of RB1-inducible coiled-coil protein 1 (RB1CC1).	[23]
Trovafloxacin	DM6AN32	Approved	Trovafloxacin increases the expression of RB1-inducible coiled-coil protein 1 (RB1CC1).	[24]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of RB1-inducible coiled-coil protein 1 (RB1CC1).	[25]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of RB1-inducible coiled-coil protein 1 (RB1CC1).	[27]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of RB1-inducible coiled-coil protein 1 (RB1CC1).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of RB1-inducible coiled-coil protein 1 (RB1CC1).	[30]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of RB1-inducible coiled-coil protein 1 (RB1CC1).	[31]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of RB1-inducible coiled-coil protein 1 (RB1CC1).	[32]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of RB1-inducible coiled-coil protein 1 (RB1CC1).	[34]
OXYBENZONE	DMMZYX6	Investigative	OXYBENZONE increases the expression of RB1-inducible coiled-coil protein 1 (RB1CC1).	[35]

References

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• [2] Tumor-suppressive functions of 15-Lipoxygenase-2 and RB1CC1 in prostate cancer.Cell Cycle. 2014;13(11):1798-810. doi: 10.4161/cc.28757. Epub 2014 Apr 14.
• [3] Downregulation of FIP200 induces apoptosis of glioblastoma cells and microvascular endothelial cells by enhancing Pyk2 activity.PLoS One. 2011;6(5):e19629. doi: 10.1371/journal.pone.0019629. Epub 2011 May 13.
• [4] Characterization of a novel anti-cancer compound for astrocytomas.PLoS One. 2014 Sep 25;9(9):e108166. doi: 10.1371/journal.pone.0108166. eCollection 2014.
• [5] Preferential expression of RB1-inducible coiled-coil 1 in terminal differentiated musculoskeletal cells.Am J Pathol. 2002 Aug;161(2):359-64. doi: 10.1016/S0002-9440(10)64190-9.
• [6] Expression of LC3B and FIP200/Atg17 in brain metastases of breast cancer.J Neurooncol. 2018 Nov;140(2):237-248. doi: 10.1007/s11060-018-2959-5. Epub 2018 Aug 9.
• [7] An integrative approach to identify YB-1-interacting proteins required for cisplatin resistance in MCF7 and MDA-MB-231 breast cancer cells. Cancer Sci. 2011 Jul;102(7):1410-7. doi: 10.1111/j.1349-7006.2011.01948.x. Epub 2011 May 5.
• [8] Screening for microsatellite instability identifies frequent 3'-untranslated region mutation of the RB1-inducible coiled-coil 1 gene in colon tumors.PLoS One. 2009 Nov 2;4(11):e7715. doi: 10.1371/journal.pone.0007715.
• [9] miR-20a inhibits hypoxia-induced autophagy by targeting ATG5/FIP200 in colorectal cancer.Mol Carcinog. 2019 Jul;58(7):1234-1247. doi: 10.1002/mc.23006. Epub 2019 Mar 18.
• [10] Evaluation of urinary autophagy transcripts expression in diabetic kidney disease.J Diabetes Complications. 2017 Oct;31(10):1491-1498. doi: 10.1016/j.jdiacomp.2017.06.009. Epub 2017 Jun 27.
• [11] Suppression of FIP200 and autophagy by tumor-derived lactate promotes nave T cell apoptosis and affects tumor immunity.Sci Immunol. 2017 Nov 17;2(17):eaan4631. doi: 10.1126/sciimmunol.aan4631.
• [12] FIP200 inhibits -catenin-mediated transcription by promoting APC-independent -catenin ubiquitination.Oncogene. 2013 May 9;32(19):2421-32. doi: 10.1038/onc.2012.262. Epub 2012 Jul 2.
• [13] PHF8 upregulation contributes to autophagic degradation of E-cadherin, epithelial-mesenchymal transition and metastasis in hepatocellular carcinoma.J Exp Clin Cancer Res. 2018 Sep 4;37(1):215. doi: 10.1186/s13046-018-0890-4.
• [14] Duplications in RB1CC1 are associated with schizophrenia; identification in large European sample sets.Transl Psychiatry. 2013 Nov 26;3(11):e326. doi: 10.1038/tp.2013.101.
• [15] RB1CC1-enhanced autophagy facilitates PSCs activation and pancreatic fibrogenesis in chronic pancreatitis.Cell Death Dis. 2018 Sep 20;9(10):952. doi: 10.1038/s41419-018-0980-4.
• [16] 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.
• [17] 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.
• [18] Gene expression data from acetaminophen-induced toxicity in human hepatic in vitro systems and clinical liver samples. Data Brief. 2016 Mar 26;7:1052-1057. doi: 10.1016/j.dib.2016.03.069. eCollection 2016 Jun.
• [19] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [20] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [21] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [22] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [23] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [24] TNF enhances trovafloxacin-induced in vitro hepatotoxicity by inhibiting protective autophagy. Toxicol Lett. 2021 May 15;342:73-84. doi: 10.1016/j.toxlet.2021.02.009. Epub 2021 Feb 17.
• [25] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [26] 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.
• [27] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [28] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [29] 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.
• [30] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [31] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [32] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [33] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.
• [34] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.
• [35] Chromatin modifiers: A new class of pollutants with potential epigenetic effects revealed by in vitro assays and transcriptomic analyses. Toxicology. 2023 Jan 15;484:153413. doi: 10.1016/j.tox.2022.153413. Epub 2022 Dec 26.