Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF8I14F)

• DOT Name: E3 ubiquitin-protein ligase RNF152 (RNF152)
• Synonyms: EC 2.3.2.27; RING finger protein 152; RING-type E3 ubiquitin transferase RNF152
• Gene Name: RNF152
• Related Disease: Colorectal carcinoma
• UniProt ID: RN152_HUMAN
• EC Number: 2.3.2.27
• Pfam ID: PF19325 ; PF14634
• Sequence:
  METLSQDSLLECQICFNYYSPRRRPKLLDCKHTCCSVCLQQMRTSQKDVRCPWCRGVTKL
  PPGFSVSQLPDDPEVLAVIAIPHTSEHTPVFIKLPSNGCYMLPLPISKERALLPGDMGCR
  LLPGSQQKSVTVVTIPAEQQPLQGGAPQEAVEEEQDRRGVVKSSTWSGVCTVILVACVLV
  FLLGIVLHNMSCISKRFTVISCG
• Function: E3 ubiquitin-protein ligase that acts as a negative regulator of mTORC1 signaling by mediating ubiquitination of RagA/RRAGA and RHEB. Catalyzes 'Lys-63'-linked polyubiquitination of RagA/RRAGA in response to amino acid starvation, thereby regulating mTORC1 signaling. Also mediates monoubiquitination of RHEB, promoting its association with the TSC-TBC complex and subsequent inhibition. Also mediates 'Lys-48'-linked polyubiquitination of target proteins and their subsequent targeting to the proteasome for degradation. Induces apoptosis when overexpressed.
• Tissue Specificity: Widely expressed.
• KEGG Pathway: mTOR sig.ling pathway (hsa04150)
• Reactome Pathway: E3 ubiquitin ligases ubiquitinate target proteins (R-HSA-8866654)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[1]

4 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of E3 ubiquitin-protein ligase RNF152 (RNF152).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the methylation of E3 ubiquitin-protein ligase RNF152 (RNF152).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of E3 ubiquitin-protein ligase RNF152 (RNF152).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of E3 ubiquitin-protein ligase RNF152 (RNF152).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of E3 ubiquitin-protein ligase RNF152 (RNF152).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein ligase RNF152 (RNF152).	[5]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of E3 ubiquitin-protein ligase RNF152 (RNF152).	[6]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of E3 ubiquitin-protein ligase RNF152 (RNF152).	[8]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of E3 ubiquitin-protein ligase RNF152 (RNF152).	[10]

References

• [1] Ring finger protein 152 inhibits colorectal cancer cell growth and is a novel prognostic biomarker.Am J Transl Res. 2018 Nov 15;10(11):3701-3712. eCollection 2018.
• [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] 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.
• [4] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [5] 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.
• [6] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [7] 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.
• [8] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [9] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [10] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.