Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6Y1DPK)

• DOT Name: Keratin, type I cytoskeletal 17 (KRT17)
• Synonyms: 39.1; Cytokeratin-17; CK-17; Keratin-17; K17
• Gene Name: KRT17
• Related Disease:
  Sebocystomatosis
  Pachyonychia congenita 2
  Pachyonychia congenita
• UniProt ID: K1C17_HUMAN
• Pfam ID: PF00038
• Sequence:
  MTTSIRQFTSSSSIKGSSGLGGGSSRTSCRLSGGLGAGSCRLGSAGGLGSTLGGSSYSSC
  YSFGSGGGYGSSFGGVDGLLAGGEKATMQNLNDRLASYLDKVRALEEANTELEVKIRDWY
  QRQAPGPARDYSQYYRTIEELQNKILTATVDNANILLQIDNARLAADDFRTKFETEQALR
  LSVEADINGLRRVLDELTLARADLEMQIENLKEELAYLKKNHEEEMNALRGQVGGEINVE
  MDAAPGVDLSRILNEMRDQYEKMAEKNRKDAEDWFFSKTEELNREVATNSELVQSGKSEI
  SELRRTMQALEIELQSQLSMKASLEGNLAETENRYCVQLSQIQGLIGSVEEQLAQLRCEM
  EQQNQEYKILLDVKTRLEQEIATYRRLLEGEDAHLTQYKKEPVTTRQVRTIVEEVQDGKV
  ISSREQVHQTTR
• Function: Type I keratin involved in the formation and maintenance of various skin appendages, specifically in determining shape and orientation of hair. Required for the correct growth of hair follicles, in particular for the persistence of the anagen (growth) state. Modulates the function of TNF-alpha in the specific context of hair cycling. Regulates protein synthesis and epithelial cell growth through binding to the adapter protein SFN and by stimulating Akt/mTOR pathway. Involved in tissue repair. May be a marker of basal cell differentiation in complex epithelia and therefore indicative of a certain type of epithelial 'stem cells'. Acts as a promoter of epithelial proliferation by acting a regulator of immune response in skin: promotes Th1/Th17-dominated immune environment contributing to the development of basaloid skin tumors. May act as an autoantigen in the immunopathogenesis of psoriasis, with certain peptide regions being a major target for autoreactive T-cells and hence causing their proliferation.
• Tissue Specificity: Expressed in the outer root sheath and medulla region of hair follicle specifically from eyebrow and beard, digital pulp, nail matrix and nail bed epithelium, mucosal stratified squamous epithelia and in basal cells of oral epithelium, palmoplantar epidermis and sweat and mammary glands. Also expressed in myoepithelium of prostate, basal layer of urinary bladder, cambial cells of sebaceous gland and in exocervix (at protein level).
• KEGG Pathway:
  Estrogen sig.ling pathway (hsa04915)
  Staphylococcus aureus infection (hsa05150)
• Reactome Pathway:
  Formation of the cornified envelope (R-HSA-6809371)
  Keratinization (R-HSA-6805567)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Sebocystomatosis	DISS9YGD	Definitive	Autosomal dominant	[1]
Pachyonychia congenita 2	DISN77SX	Strong	Autosomal dominant	[2]
Pachyonychia congenita	DISW8VPN	Supportive	Autosomal dominant	[3]

2 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 Keratin, type I cytoskeletal 17 (KRT17).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Keratin, type I cytoskeletal 17 (KRT17).	[24]

30 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 Keratin, type I cytoskeletal 17 (KRT17).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Keratin, type I cytoskeletal 17 (KRT17).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Keratin, type I cytoskeletal 17 (KRT17).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Keratin, type I cytoskeletal 17 (KRT17).	[8]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Keratin, type I cytoskeletal 17 (KRT17).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Keratin, type I cytoskeletal 17 (KRT17).	[10]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Keratin, type I cytoskeletal 17 (KRT17).	[11]
Selenium	DM25CGV	Approved	Selenium increases the expression of Keratin, type I cytoskeletal 17 (KRT17).	[12]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Keratin, type I cytoskeletal 17 (KRT17).	[13]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of Keratin, type I cytoskeletal 17 (KRT17).	[14]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Keratin, type I cytoskeletal 17 (KRT17).	[6]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Keratin, type I cytoskeletal 17 (KRT17).	[15]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Keratin, type I cytoskeletal 17 (KRT17).	[16]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Keratin, type I cytoskeletal 17 (KRT17).	[17]
Simvastatin	DM30SGU	Approved	Simvastatin increases the expression of Keratin, type I cytoskeletal 17 (KRT17).	[18]
Alitretinoin	DMME8LH	Approved	Alitretinoin decreases the expression of Keratin, type I cytoskeletal 17 (KRT17).	[6]
Bexarotene	DMOBIKY	Approved	Bexarotene decreases the expression of Keratin, type I cytoskeletal 17 (KRT17).	[19]
Calcipotriol	DM03CP7	Approved	Calcipotriol decreases the expression of Keratin, type I cytoskeletal 17 (KRT17).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Keratin, type I cytoskeletal 17 (KRT17).	[20]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Keratin, type I cytoskeletal 17 (KRT17).	[21]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Keratin, type I cytoskeletal 17 (KRT17).	[15]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Keratin, type I cytoskeletal 17 (KRT17).	[22]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Keratin, type I cytoskeletal 17 (KRT17).	[25]
SB-431542	DM0YOXQ	Preclinical	SB-431542 increases the expression of Keratin, type I cytoskeletal 17 (KRT17).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Keratin, type I cytoskeletal 17 (KRT17).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Keratin, type I cytoskeletal 17 (KRT17).	[27]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Keratin, type I cytoskeletal 17 (KRT17).	[28]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Keratin, type I cytoskeletal 17 (KRT17).	[29]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Keratin, type I cytoskeletal 17 (KRT17).	[30]
all-trans-4-oxo-retinoic acid	DMM2R1N	Investigative	all-trans-4-oxo-retinoic acid decreases the expression of Keratin, type I cytoskeletal 17 (KRT17).	[6]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Keratin, type I cytoskeletal 17 (KRT17).	[23]

References

• [1] Missense mutations in keratin 17 cause either pachyonychia congenita type 2 or a phenotype resembling steatocystoma multiplex. J Invest Dermatol. 1997 Feb;108(2):220-3. doi: 10.1111/1523-1747.ep12335315.
• [2] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [3] Pachyonychia Congenita. 2006 Jan 27 [updated 2017 Nov 30]. 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.
• [4] 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.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] Retinoic acid and its 4-oxo metabolites are functionally active in human skin cells in vitro. J Invest Dermatol. 2005 Jul;125(1):143-53.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [9] 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.
• [10] Effects of 1 alpha,25-dihydroxy-vitamin D3 and calcipotriol on organotypic cultures of outer root sheath cells: a potential model to evaluate antipsoriatic drugs. Arch Dermatol Res. 1993;285(7):402-9. doi: 10.1007/BF00372133.
• [11] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [12] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [13] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [14] Multi-level gene expression profiles affected by thymidylate synthase and 5-fluorouracil in colon cancer. BMC Genomics. 2006 Apr 3;7:68. doi: 10.1186/1471-2164-7-68.
• [15] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [16] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [17] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [18] Simvastatin inactivates beta1-integrin and extracellular signal-related kinase signaling and inhibits cell proliferation in head and neck squamous cell carcinoma cells. Cancer Sci. 2007 Jun;98(6):890-9.
• [19] Identification of biomarkers modulated by the rexinoid LGD1069 (bexarotene) in human breast cells using oligonucleotide arrays. Cancer Res. 2006 Dec 15;66(24):12009-18.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [22] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [23] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [24] 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.
• [25] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [26] Activin/nodal signaling switches the terminal fate of human embryonic stem cell-derived trophoblasts. J Biol Chem. 2015 Apr 3;290(14):8834-48.
• [27] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [28] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [29] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [30] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.