Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTN7FCDE)

• DOT Name: E3 ubiquitin-protein ligase RNF144B (RNF144B)
• Synonyms: EC 2.3.2.31; IBR domain-containing protein 2; RING finger protein 144B; p53-inducible RING finger protein
• Gene Name: RNF144B
• Related Disease:
  Chordoma
  Endometrial cancer
  Endometrial carcinoma
  Endometrium neoplasm
• UniProt ID: R144B_HUMAN
• EC Number: 2.3.2.31
• Pfam ID: PF01485
• Sequence:
  MGSAGRLHYLAMTAENPTPGDLAPAPLITCKLCLCEQSLDKMTTLQECQCIFCTACLKQY
  MQLAIREGCGSPITCPDMVCLNHGTLQEAEIACLVPVDQFQLYQRLKFEREVHLDPYRTW
  CPVADCQTVCPVASSDPGQPVLVECPSCHLKFCSCCKDAWHAEVSCRDSQPIVLPTEHRA
  LFGTDAEAPIKQCPVCRVYIERNEGCAQMMCKNCKHTFCWYCLQNLDNDIFLRHYDKGPC
  RNKLGHSRASVMWNRTQVVGILVGLGIIALVTSPLLLLASPCIICCVCKSCRGKKKKHDP
  STT
• Function: E3 ubiquitin-protein ligase which accepts ubiquitin from E2 ubiquitin-conjugating enzymes UBE2L3 and UBE2L6 in the form of a thioester and then directly transfers the ubiquitin to targeted substrates such as LCMT2, thereby promoting their degradation. Induces apoptosis via a p53/TP53-dependent but caspase-independent mechanism. However, its overexpression also produces a decrease of the ubiquitin-dependent stability of BAX, a pro-apoptotic protein, ultimately leading to protection of cell death; But, it is not an anti-apoptotic protein per se.
• Tissue Specificity: Broadly expressed, with lowest levels in brain and thymus, and highest levels detectable in heart, ovary and testis.
• Reactome Pathway: Antigen processing (R-HSA-983168)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chordoma	DISCHJE7	Strong	Altered Expression	[1]
Endometrial cancer	DISW0LMR	Strong	Biomarker	[2]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[2]
Endometrium neoplasm	DIS6OS2L	Strong	Biomarker	[2]

22 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 E3 ubiquitin-protein ligase RNF144B (RNF144B).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of E3 ubiquitin-protein ligase RNF144B (RNF144B).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of E3 ubiquitin-protein ligase RNF144B (RNF144B).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of E3 ubiquitin-protein ligase RNF144B (RNF144B).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein ligase RNF144B (RNF144B).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of E3 ubiquitin-protein ligase RNF144B (RNF144B).	[8]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of E3 ubiquitin-protein ligase RNF144B (RNF144B).	[9]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of E3 ubiquitin-protein ligase RNF144B (RNF144B).	[10]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of E3 ubiquitin-protein ligase RNF144B (RNF144B).	[11]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of E3 ubiquitin-protein ligase RNF144B (RNF144B).	[12]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of E3 ubiquitin-protein ligase RNF144B (RNF144B).	[13]
Rofecoxib	DM3P5DA	Approved	Rofecoxib increases the expression of E3 ubiquitin-protein ligase RNF144B (RNF144B).	[14]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of E3 ubiquitin-protein ligase RNF144B (RNF144B).	[11]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of E3 ubiquitin-protein ligase RNF144B (RNF144B).	[11]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of E3 ubiquitin-protein ligase RNF144B (RNF144B).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of E3 ubiquitin-protein ligase RNF144B (RNF144B).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of E3 ubiquitin-protein ligase RNF144B (RNF144B).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of E3 ubiquitin-protein ligase RNF144B (RNF144B).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of E3 ubiquitin-protein ligase RNF144B (RNF144B).	[21]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of E3 ubiquitin-protein ligase RNF144B (RNF144B).	[9]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of E3 ubiquitin-protein ligase RNF144B (RNF144B).	[22]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of E3 ubiquitin-protein ligase RNF144B (RNF144B).	[23]

1 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 decreases the methylation of E3 ubiquitin-protein ligase RNF144B (RNF144B).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
AZD-1080	DMIM9N1	Discontinued in Phase 1	AZD-1080 increases the degradation of E3 ubiquitin-protein ligase RNF144B (RNF144B).	[2]
MG-132	DMKA2YS	Preclinical	MG-132 decreases the degradation of E3 ubiquitin-protein ligase RNF144B (RNF144B).	[2]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride increases the degradation of E3 ubiquitin-protein ligase RNF144B (RNF144B).	[2]

References

• [1] Long non-coding RNA LOC554202 modulates chordoma cell proliferation and invasion by recruiting EZH2 and regulating miR-31 expression.Cell Prolif. 2017 Dec;50(6):e12388. doi: 10.1111/cpr.12388. Epub 2017 Sep 30.
• [2] Pir2/Rnf144b is a potential endometrial cancer biomarker that promotes cell proliferation. Cell Death Dis. 2018 May 1;9(5):504. doi: 10.1038/s41419-018-0521-1.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [5] 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.
• [6] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [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] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [10] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [11] 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.
• [12] Mechanisms of indomethacin-induced alterations in the choline phospholipid metabolism of breast cancer cells. Neoplasia. 2006 Sep;8(9):758-71.
• [13] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [14] Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain. Pain. 2007 Mar;128(1-2):136-47.
• [15] 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.
• [16] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [17] 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.
• [18] Pir2/Rnf144b is a potential endometrial cancer biomarker that promotes cell proliferation. Cell Death Dis. 2018 May 1;9(5):504. doi: 10.1038/s41419-018-0521-1.
• [19] Bisphenol A Analogues Suppress Spheroid Attachment on Human Endometrial Epithelial Cells through Modulation of Steroid Hormone Receptors Signaling Pathway. Cells. 2021 Oct 26;10(11):2882. doi: 10.3390/cells10112882.
• [20] 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.
• [21] Cystathionine metabolic enzymes play a role in the inflammation resolution of human keratinocytes in response to sub-cytotoxic formaldehyde exposure. Toxicol Appl Pharmacol. 2016 Nov 1;310:185-194.
• [22] 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.
• [23] Persistence of epigenomic effects after recovery from repeated treatment with two nephrocarcinogens. Front Genet. 2018 Dec 3;9:558.