Details of Drug Off-Target (DOT)

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

• DOT Name: RING finger protein 11 (RNF11)
• Gene Name: RNF11
• Related Disease:
  Advanced cancer
  Barrett esophagus
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Parkinson disease
  Neuroblastoma
• UniProt ID: RNF11_HUMAN
• Pfam ID: PF13639
• Sequence:
  MGNCLKSPTSDDISLLHESQSDRASFGEGTEPDQEPPPPYQEQVPVPVYHPTPSQTRLAT
  QLTEEEQIRIAQRIGLIQHLPKGVYDPGRDGSEKKIRECVICMMDFVYGDPIRFLPCMHI
  YHLDCIDDWLMRSFTCPSCMEPVDAALLSSYETN
• Function: Essential component of a ubiquitin-editing protein complex, comprising also TNFAIP3, ITCH and TAX1BP1, that ensures the transient nature of inflammatory signaling pathways. Promotes the association of TNFAIP3 to RIPK1 after TNF stimulation. TNFAIP3 deubiquitinates 'Lys-63' polyubiquitin chains on RIPK1 and catalyzes the formation of 'Lys-48'-polyubiquitin chains. This leads to RIPK1 proteasomal degradation and consequently termination of the TNF- or LPS-mediated activation of NF-kappa-B. Recruits STAMBP to the E3 ubiquitin-ligase SMURF2 for ubiquitination, leading to its degradation by the 26S proteasome.
• Tissue Specificity: Expressed at low levels in the lung, liver, kidney, pancreas, spleen, prostate, thymus, ovary, small intestine, colon, and peripheral blood lymphocytes, and, at intermediate levels, in the testis, heart, brain and placenta. Highest expression in the skeletal muscle. In the brain, expressed at different levels in several regions: high levels in the amygdala, moderate in the hippocampus and thalamus, low in the caudate and extremely low levels in the corpus callosum (at protein level). Restricted to neurons, enriched in somatodendritic compartments and excluded from white matter (at protein level). In substantia nigra, present in cell bodies and processes of dopaminergic and nondopaminergic cells (at protein level). In Parkinson disease, sequestered in Lewy bodies and neurites. Overexpressed in breast cancer cells, but not detected in the surrounding stroma and weakly, if at all, in normal breast epithelial cells (at protein level). Also expressed in several tumor cell lines.

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Barrett esophagus	DIS416Y7	Strong	Altered Expression	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[1]
Parkinson disease	DISQVHKL	Strong	Genetic Variation	[4]
Neuroblastoma	DISVZBI4	Limited	Genetic Variation	[5]

8 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 RING finger protein 11 (RNF11).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of RING finger protein 11 (RNF11).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of RING finger protein 11 (RNF11).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of RING finger protein 11 (RNF11).	[9]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of RING finger protein 11 (RNF11).	[10]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of RING finger protein 11 (RNF11).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of RING finger protein 11 (RNF11).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of RING finger protein 11 (RNF11).	[14]

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 increases the methylation of RING finger protein 11 (RNF11).	[12]

References

• [1] RNF11 is a multifunctional modulator of growth factor receptor signalling and transcriptional regulation.Eur J Cancer. 2005 Nov;41(16):2549-60. doi: 10.1016/j.ejca.2005.08.020. Epub 2005 Oct 13.
• [2] RING finger proteins are involved in the progression of barrett esophagus to esophageal adenocarcinoma: a preliminary study.Gut Liver. 2014 Sep;8(5):487-94. doi: 10.5009/gnl13133. Epub 2014 Feb 24.
• [3] The WW domain containing E3 ubiquitin protein ligase 1 upregulates ErbB2 and EGFR through RING finger protein 11.Oncogene. 2008 Nov 20;27(54):6845-55. doi: 10.1038/onc.2008.288. Epub 2008 Aug 25.
• [4] Association mapping of the PARK10 region for Parkinson's disease susceptibility genes.Parkinsonism Relat Disord. 2014 Jan;20(1):93-8. doi: 10.1016/j.parkreldis.2013.10.001. Epub 2013 Oct 11.
• [5] Focal DNA copy number changes in neuroblastoma target MYCN regulated genes.PLoS One. 2013;8(1):e52321. doi: 10.1371/journal.pone.0052321. Epub 2013 Jan 4.
• [6] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] 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.
• [13] 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.
• [14] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.