Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3CL4R3)

• DOT Name: Ribosomal L1 domain-containing protein 1 (RSL1D1)
• Synonyms: CATX-11; Cellular senescence-inhibited gene protein; Protein PBK1
• Gene Name: RSL1D1
• Related Disease:
  Hepatocellular carcinoma
  Lung cancer
  Lung carcinoma
  Brucellosis
• UniProt ID: RL1D1_HUMAN
• PDB ID: 8FKP; 8FKQ; 8FKR; 8FKS; 8FKT; 8FKU; 8FKV; 8FKW; 8FKX; 8FKY; 8FKZ; 8FL2; 8FL6; 8FLA; 8FLD; 8INE; 8INF; 8IPX; 8IPY; 8IR3
• Pfam ID: PF00687
• Sequence:
  MEDSASASLSSAAATGTSTSTPAAPTARKQLDKEQVRKAVDALLTHCKSRKNNYGLLLNE
  NESLFLMVVLWKIPSKELRVRLTLPHSIRSDSEDICLFTKDEPNSTPEKTEQFYRKLLNK
  HGIKTVSQIISLQTLKKEYKSYEAKLRLLSSFDFFLTDARIRRLLPSLIGRHFYQRKKVP
  VSVNLLSKNLSREINDCIGGTVLNISKSGSCSAIRIGHVGMQIEHIIENIVAVTKGLSEK
  LPEKWESVKLLFVKTEKSAALPIFSSFVSNWDEATKRSLLNKKKKEARRKRRERNFEKQK
  ERKKKRQQARKTASVLSKDDVAPESGDTTVKKPESKKEQTPEHGKKKRGRGKAQVKATNE
  SEDEIPQLVPIGKKTPANEKVEIQKHATGKKSPAKSPNPSTPRGKKRKALPASETPKAAE
  SETPGKSPEKKPKIKEEAVKEKSPSLGKKDARQTPKKPEAKFFTTPSKSVRKASHTPKKW
  PKKPKVPQST
• Function: Regulates cellular senescence through inhibition of PTEN translation. Acts as a pro-apoptotic regulator in response to DNA damage.
• Tissue Specificity: Expressed at high intensities in the heart, skeletal muscle, and placenta.

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[1]
Lung cancer	DISCM4YA	Strong	Biomarker	[2]
Lung carcinoma	DISTR26C	Strong	Biomarker	[2]
Brucellosis	DISEAYGH	Disputed	Biomarker	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Ribosomal L1 domain-containing protein 1 (RSL1D1).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Ribosomal L1 domain-containing protein 1 (RSL1D1).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Ribosomal L1 domain-containing protein 1 (RSL1D1).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ribosomal L1 domain-containing protein 1 (RSL1D1).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Ribosomal L1 domain-containing protein 1 (RSL1D1).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Ribosomal L1 domain-containing protein 1 (RSL1D1).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ribosomal L1 domain-containing protein 1 (RSL1D1).	[10]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Ribosomal L1 domain-containing protein 1 (RSL1D1).	[11]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Ribosomal L1 domain-containing protein 1 (RSL1D1).	[12]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Ribosomal L1 domain-containing protein 1 (RSL1D1).	[13]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Ribosomal L1 domain-containing protein 1 (RSL1D1).	[14]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Ribosomal L1 domain-containing protein 1 (RSL1D1).	[15]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Ribosomal L1 domain-containing protein 1 (RSL1D1).	[16]
Cidofovir	DMA13GD	Approved	Cidofovir affects the expression of Ribosomal L1 domain-containing protein 1 (RSL1D1).	[9]
Ibuprofen	DM8VCBE	Approved	Ibuprofen increases the expression of Ribosomal L1 domain-containing protein 1 (RSL1D1).	[9]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN affects the expression of Ribosomal L1 domain-containing protein 1 (RSL1D1).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Ribosomal L1 domain-containing protein 1 (RSL1D1).	[21]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Ribosomal L1 domain-containing protein 1 (RSL1D1).	[14]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Ribosomal L1 domain-containing protein 1 (RSL1D1).	[22]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE increases the expression of Ribosomal L1 domain-containing protein 1 (RSL1D1).	[11]

4 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 Ribosomal L1 domain-containing protein 1 (RSL1D1).	[17]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Ribosomal L1 domain-containing protein 1 (RSL1D1).	[18]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Ribosomal L1 domain-containing protein 1 (RSL1D1).	[19]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Ribosomal L1 domain-containing protein 1 (RSL1D1).	[19]

References

• [1] CSIG promotes hepatocellular carcinoma proliferation by activating c-MYC expression.Oncotarget. 2015 Mar 10;6(7):4733-44. doi: 10.18632/oncotarget.2900.
• [2] Identification of a novel nucleus protein involved in the regulation of urokinase in 95D cells.Acta Biochim Biophys Sin (Shanghai). 2005 May;37(5):303-9. doi: 10.1111/j.1745-7270.2005.00041.x.
• [3] Escheriosome-mediated delivery of recombinant ribosomal L7/L12 protein confers protection against murine brucellosis.Vaccine. 2007 Nov 14;25(46):7873-84. doi: 10.1016/j.vaccine.2007.09.008. Epub 2007 Sep 20.
• [4] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [5] 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.
• [6] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [10] 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.
• [11] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [12] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [13] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [14] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [15] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [16] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [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] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [19] 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.
• [20] DON shares a similar mode of action as the ribotoxic stress inducer anisomycin while TBTO shares ER stress patterns with the ER stress inducer thapsigargin based on comparative gene expression profiling in Jurkat T cells. Toxicol Lett. 2014 Jan 30;224(3):395-406. doi: 10.1016/j.toxlet.2013.11.005. Epub 2013 Nov 15.
• [21] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [22] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.