Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7QIJ0X)

• DOT Name: Transcription factor CP2-like protein 1 (TFCP2L1)
• Synonyms: CP2-related transcriptional repressor 1; CRTR-1; Transcription factor LBP-9
• Gene Name: TFCP2L1
• Related Disease:
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid tumor
  Advanced cancer
  Behcet disease
  Clear cell renal carcinoma
  Renal cell carcinoma
  Testicular germ cell tumor
  Thyroid gland undifferentiated (anaplastic) carcinoma
  Triple negative breast cancer
  Neoplasm
  Urinary bladder cancer
  Thyroid gland papillary carcinoma
• UniProt ID: TF2L1_HUMAN
• Pfam ID: PF04516 ; PF18016
• Sequence:
  MLFWHTQPEHYNQHNSGSYLRDVLALPIFKQEEPQLSPENEARLPPLQYVLCAATSPAVK
  LHEETLTYLNQGQSYEIRLLENRKLGDFQDLNTKYVKSIIRVVFHDRRLQYTEHQQLEGW
  RWSRPGDRILDIDIPLSVGILDPRASPTQLNAVEFLWDPAKRASAFIQVHCISTEFTPRK
  HGGEKGVPFRVQIDTFKQNENGEYTEHLHSASCQIKVFKPKGADRKQKTDREKMEKRTAQ
  EKEKYQPSYETTILTECSPWPDVAYQVNSAPSPSYNGSPNSFGLGEGNASPTHPVEALPV
  GSDHLLPSASIQDAQQWLHRNRFSQFCRLFASFSGADLLKMSRDDLVQICGPADGIRLFN
  AIKGRNVRPKMTIYVCQELEQNRVPLQQKRDGSGDSNLSVYHAIFLEELTTLELIEKIAN
  LYSISPQHIHRVYRQGPTGIHVVVSNEMVQNFQDESCFVLSTIKAESNDGYHIILKCGL
• Function: Transcription factor that facilitates establishment and maintenance of pluripotency in embryonic stem cells (ESCs). With KLF2, acts as the major effector of self-renewal that mediates induction of pluripotency downstream of LIF/STAT3 and Wnt/beta-catenin signaling. Required for normal duct development in the salivary gland and kidney. Coordinates the development of the kidney collecting ducts intercalated (IC) and principal (PC) cells, which regulate acid-base and salt-water homeostasis, respectively. Regulates the expression of IC genes including subunits B1 and D2 of the V-ATPase complex, OXGR1, CA12, SLC4A1, AQP6 and IC-specific transcription factor FOXI1. Regulates also the expression of JAG1 and subsequent notch signaling in the collecting duct. JAG1 initiates notch signaling in PCs but inhibits notch signaling in ICs. Acts as a transcriptional suppressor that may suppress UBP1-mediated transcriptional activation. Modulates the placental expression of CYP11A1.
• Tissue Specificity: Highly expressed in placental JEG-3 cells and very low levels of expression in non-steroidogenic cells. No expression was seen in adrenal NCI-H295A cells or in adrenal tissue.

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Thyroid cancer	DIS3VLDH	Definitive	Biomarker	[1]
Thyroid gland carcinoma	DISMNGZ0	Definitive	Biomarker	[1]
Thyroid tumor	DISLVKMD	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Behcet disease	DISSYMBS	Strong	Genetic Variation	[2]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[1]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[3]
Testicular germ cell tumor	DIS5RN24	Strong	Biomarker	[4]
Thyroid gland undifferentiated (anaplastic) carcinoma	DISYBB1W	Strong	Altered Expression	[5]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	moderate	Altered Expression	[7]
Urinary bladder cancer	DISDV4T7	moderate	Posttranslational Modification	[7]
Thyroid gland papillary carcinoma	DIS48YMM	Limited	Biomarker	[8]

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 Transcription factor CP2-like protein 1 (TFCP2L1).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Transcription factor CP2-like protein 1 (TFCP2L1).	[10]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Transcription factor CP2-like protein 1 (TFCP2L1).	[11]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Transcription factor CP2-like protein 1 (TFCP2L1).	[12]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Transcription factor CP2-like protein 1 (TFCP2L1).	[13]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Transcription factor CP2-like protein 1 (TFCP2L1).	[14]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Transcription factor CP2-like protein 1 (TFCP2L1).	[9]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Transcription factor CP2-like protein 1 (TFCP2L1).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Transcription factor CP2-like protein 1 (TFCP2L1).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Transcription factor CP2-like protein 1 (TFCP2L1).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Transcription factor CP2-like protein 1 (TFCP2L1).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Transcription factor CP2-like protein 1 (TFCP2L1).	[20]

2 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 increases the methylation of Transcription factor CP2-like protein 1 (TFCP2L1).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Transcription factor CP2-like protein 1 (TFCP2L1).	[18]

References

• [1] TFCP2/TFCP2L1/UBP1 transcription factors in cancer.Cancer Lett. 2018 Apr 28;420:72-79. doi: 10.1016/j.canlet.2018.01.078. Epub 2018 Feb 7.
• [2] Identification of a susceptibility locus in STAT4 for Behet's disease in Han Chinese in a genome-wide association study.Arthritis Rheum. 2012 Dec;64(12):4104-13. doi: 10.1002/art.37708.
• [3] New miRNA profiles accurately distinguish renal cell carcinomas and upper tract urothelial carcinomas from the normal kidney.PLoS One. 2014 Mar 12;9(3):e91646. doi: 10.1371/journal.pone.0091646. eCollection 2014.
• [4] Validation of loci at 2q14.2 and 15q21.3 as risk factors for testicular cancer.Oncotarget. 2017 Dec 7;9(16):12630-12638. doi: 10.18632/oncotarget.23117. eCollection 2018 Feb 27.
• [5] Differential expression of alphaB-crystallin and Hsp27-1 in anaplastic thyroid carcinomas because of tumor-specific alphaB-crystallin gene (CRYAB) silencing.Cell Stress Chaperones. 2005 Autumn;10(3):171-84. doi: 10.1379/csc-107r.1.
• [6] Circ-TFCP2L1 Promotes the Proliferation and Migration of Triple Negative Breast Cancer through Sponging miR-7 by Inhibiting PAK1.J Mammary Gland Biol Neoplasia. 2019 Dec;24(4):323-331. doi: 10.1007/s10911-019-09440-4. Epub 2019 Nov 27.
• [7] Phosphorylation of TFCP2L1 by CDK1 is required for stem cell pluripotency and bladder carcinogenesis.EMBO Mol Med. 2020 Jan 9;12(1):e10880. doi: 10.15252/emmm.201910880. Epub 2019 Nov 11.
• [8] Microarray analysis of papillary thyroid cancers in Korean.Korean J Intern Med. 2010 Dec;25(4):399-407. doi: 10.3904/kjim.2010.25.4.399. Epub 2010 Nov 27.
• [9] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] 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.
• [12] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [13] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [14] Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. 2011 Jul;26(7):1813-25.
• [15] Gene expression signatures after ethanol exposure in differentiating embryoid bodies. Toxicol In Vitro. 2018 Feb;46:66-76.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] 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.
• [18] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [19] 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.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.