Details of Drug Off-Target (DOT)

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

• DOT Name: PIH1 domain-containing protein 1 (PIH1D1)
• Synonyms: Nucleolar protein 17 homolog
• Gene Name: PIH1D1
• Related Disease:
  Breast cancer
  Breast carcinoma
• UniProt ID: PIHD1_HUMAN
• PDB ID: 4PSF; 4PSI; 6GXZ; 7AVC; 8BDU
• Pfam ID: PF08190 ; PF18201
• Sequence:
  MANPKLLGMGLSEAEAIGADSARFEELLLQASKELQQAQTTRPESTQIQPQPGFCIKTNS
  SEGKVFINICHSPSIPPPADVTEEELLQMLEEDQAGFRIPMSLGEPHAELDAKGQGCTAY
  DVAVNSDFYRRMQNSDFLRELVITIAREGLEDKYNLQLNPEWRMMKNRPFMGSISQQNIR
  SEQRPRIQELGDLYTPAPGRAESGPEKPHLNLWLEAPDLLLAEVDLPKLDGALGLSLEIG
  ENRLVMGGPQQLYHLDAYIPLQINSHESKAAFHRKRKQLMVAMPLLPVPS
• Function: Involved in the assembly of C/D box small nucleolar ribonucleoprotein (snoRNP) particles. Recruits the SWI/SNF complex to the core promoter of rRNA genes and enhances pre-rRNA transcription. Mediates interaction of TELO2 with the R2TP complex which is necessary for the stability of MTOR and SMG1. Positively regulates the assembly and activity of the mTORC1 complex.
• Tissue Specificity: Expressed at low levels in normal mammary epithelial cells (at protein level) . Highest expression in lung, leukocyte and placenta. Expressed at lower levels in brain, prostate, colon, heart, small intestine, liver, ovary, pancreas, skeletal muscle, spleen, testis and thymus .

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Limited	Biomarker	[1]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[1]

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 PIH1 domain-containing protein 1 (PIH1D1).	[2]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of PIH1 domain-containing protein 1 (PIH1D1).	[10]

11 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 PIH1 domain-containing protein 1 (PIH1D1).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of PIH1 domain-containing protein 1 (PIH1D1).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of PIH1 domain-containing protein 1 (PIH1D1).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of PIH1 domain-containing protein 1 (PIH1D1).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of PIH1 domain-containing protein 1 (PIH1D1).	[7]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of PIH1 domain-containing protein 1 (PIH1D1).	[8]
Selenium	DM25CGV	Approved	Selenium increases the expression of PIH1 domain-containing protein 1 (PIH1D1).	[9]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of PIH1 domain-containing protein 1 (PIH1D1).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of PIH1 domain-containing protein 1 (PIH1D1).	[11]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of PIH1 domain-containing protein 1 (PIH1D1).	[12]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of PIH1 domain-containing protein 1 (PIH1D1).	[13]

References

• [1] PIH1D1 interacts with mTOR complex 1 and enhances ribosome RNA transcription.FEBS Lett. 2013 Oct 11;587(20):3303-8. doi: 10.1016/j.febslet.2013.09.001. Epub 2013 Sep 11.
• [2] 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.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [7] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [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] 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.
• [10] 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.
• [11] 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.
• [12] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [13] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.