Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG5URO4)

• DOT Name: Large ribosomal subunit protein mL41 (MRPL41)
• Synonyms: 39S ribosomal protein L41, mitochondrial; L41mt; MRP-L41; Bcl-2-interacting mitochondrial ribosomal protein L41; Cell proliferation-inducing gene 3 protein; MRP-L27 homolog
• Gene Name: MRPL41
• Related Disease:
  Bladder cancer
  Carcinoma
  Clear cell renal carcinoma
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Ewing sarcoma
  Gastric cancer
  Head-neck squamous cell carcinoma
  Lung adenocarcinoma
  Neoplasm
  Non-small-cell lung cancer
  Renal cell carcinoma
  Stomach cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
  Breast cancer
  Breast carcinoma
  Prostate cancer
  Prostate carcinoma
  Adult glioblastoma
  Glioblastoma multiforme
  Melanoma
  Thyroid gland papillary carcinoma
• UniProt ID: RM41_HUMAN
• PDB ID: 3J7Y ; 3J9M ; 5OOL ; 5OOM ; 6I9R ; 6NU2 ; 6NU3 ; 6VLZ ; 6VMI ; 6ZM5 ; 6ZM6 ; 6ZS9 ; 6ZSA ; 6ZSB ; 6ZSC ; 6ZSD ; 6ZSE ; 6ZSG ; 7A5F ; 7A5G ; 7A5H ; 7A5I ; 7A5J ; 7A5K ; 7L08 ; 7L20 ; 7O9K ; 7O9M ; 7ODR ; 7ODS ; 7ODT ; 7OF0 ; 7OF2 ; 7OF3 ; 7OF4 ; 7OF5 ; 7OF6 ; 7OF7 ; 7OG4 ; 7OI6 ; 7OI7 ; 7OI8 ; 7OI9 ; 7OIA ; 7OIB ; 7OIC ; 7OID ; 7OIE ; 7PD3 ; 7PO4 ; 7QH6 ; 7QH7 ; 7QI4 ; 7QI5 ; 7QI6 ; 8ANY ; 8OIR ; 8OIT
• Pfam ID: PF09809
• Sequence:
  MGVLAAAARCLVRGADRMSKWTSKRGPRSFRGRKGRGAKGIGFLTSGWRFVQIKEMVPEF
  VVPDLTGFKLKPYVSYLAPESEETPLTAAQLFSEAVAPAIEKDFKDGTFDPDNLEKYGFE
  PTQEGKLFQLYPRNFLR
• Function: Component of the mitochondrial ribosome large subunit. Also involved in apoptosis and cell cycle. Enhances p53/TP53 stability, thereby contributing to p53/TP53-induced apoptosis in response to growth-inhibitory condition. Enhances p53/TP53 translocation to the mitochondria. Has the ability to arrest the cell cycle at the G1 phase, possibly by stabilizing the CDKN1A and CDKN1B (p27Kip1) proteins.
• Tissue Specificity: Present in kidney, liver, thymus and testis, and at lower level in brain and spleen (at protein level).
• Reactome Pathway:
  Mitochondrial translation elongation (R-HSA-5389840)
  Mitochondrial translation termination (R-HSA-5419276)
  Mitochondrial translation initiation (R-HSA-5368286)

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bladder cancer	DISUHNM0	Strong	Genetic Variation	[1]
Carcinoma	DISH9F1N	Strong	Genetic Variation	[2]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[3]
Colon cancer	DISVC52G	Strong	Biomarker	[4]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[5]
Ewing sarcoma	DISQYLV3	Strong	Genetic Variation	[6]
Gastric cancer	DISXGOUK	Strong	Biomarker	[7]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Genetic Variation	[8]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[9]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[9]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[3]
Stomach cancer	DISKIJSX	Strong	Biomarker	[7]
Urinary bladder cancer	DISDV4T7	Strong	Genetic Variation	[1]
Urinary bladder neoplasm	DIS7HACE	Strong	Genetic Variation	[1]
Breast cancer	DIS7DPX1	moderate	Altered Expression	[10]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[10]
Prostate cancer	DISF190Y	moderate	Biomarker	[11]
Prostate carcinoma	DISMJPLE	moderate	Biomarker	[11]
Adult glioblastoma	DISVP4LU	Limited	Biomarker	[12]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[12]
Melanoma	DIS1RRCY	Limited	Biomarker	[13]
Thyroid gland papillary carcinoma	DIS48YMM	Limited	Biomarker	[14]

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 Large ribosomal subunit protein mL41 (MRPL41).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Large ribosomal subunit protein mL41 (MRPL41).	[20]

4 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 Large ribosomal subunit protein mL41 (MRPL41).	[16]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Large ribosomal subunit protein mL41 (MRPL41).	[17]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Large ribosomal subunit protein mL41 (MRPL41).	[18]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Large ribosomal subunit protein mL41 (MRPL41).	[19]

References

• [1] Association of the PIG3 promoter polymorphism with invasive bladder cancer in a Japanese population.Jpn J Clin Oncol. 2006 Feb;36(2):116-20. doi: 10.1093/jjco/hyi225. Epub 2006 Jan 17.
• [2] Absence of association with cancer risk and low frequency of alterations at a p53 responsive PIG3 gene polymorphism in breast and lung carcinomas.Mutat Res. 2004 Nov 22;556(1-2):143-50. doi: 10.1016/j.mrfmmm.2004.07.008.
• [3] Loss of PIG3 increases HIF-1 level by promoting protein synthesis via mTOR pathway in renal cell carcinoma cells.Oncotarget. 2016 May 10;7(19):27176-84. doi: 10.18632/oncotarget.8401.
• [4] The oncogenic effects of p53-inducible gene 3 (PIG3) in colon cancer cells.Korean J Physiol Pharmacol. 2017 Mar;21(2):267-273. doi: 10.4196/kjpp.2017.21.2.267. Epub 2017 Feb 21.
• [5] HPIP is upregulated in colorectal cancer and regulates colorectal cancer cell proliferation, apoptosis and invasion.Sci Rep. 2015 Mar 24;5:9429. doi: 10.1038/srep09429.
• [6] Constitutive and DNA damage inducible activation of pig3 and MDM2 genes by tumor-derived p53 mutant C277Y.Mol Cancer Res. 2004 May;2(5):296-304.
• [7] PIG3 suppresses gastric cancer proliferation by regulating p53- mediated apoptosis.J Biol Regul Homeost Agents. 2018 Sep-Oct;32(5):1185-1189.
• [8] Functional repeats (TGYCC)n in the p53-inducible gene 3 (PIG3) promoter and susceptibility to squamous cell carcinoma of the head and neck.Carcinogenesis. 2013 Apr;34(4):812-7. doi: 10.1093/carcin/bgs388. Epub 2012 Dec 14.
• [9] p53-inducible gene 3 promotes cell migration and invasion by activating the FAK/Src pathway in lung adenocarcinoma.Cancer Sci. 2018 Dec;109(12):3783-3793. doi: 10.1111/cas.13818. Epub 2018 Oct 26.
• [10] BRCA1 regulates PIG3-mediated apoptosis in a p53-dependent manner.Oncotarget. 2015 Apr 10;6(10):7608-18. doi: 10.18632/oncotarget.3263.
• [11] p53-induced gene 3 mediates cell death induced by glutathione peroxidase 3.J Biol Chem. 2012 May 11;287(20):16890-902. doi: 10.1074/jbc.M111.322636. Epub 2012 Mar 29.
• [12] Suppression of p53-inducible gene 3 is significant for glioblastoma progression and predicts poor patient prognosis.Tumour Biol. 2017 Mar;39(3):1010428317694572. doi: 10.1177/1010428317694572.
• [13] Reactivation of p53 by a Cytoskeletal Sensor to Control the Balance Between DNA Damage and Tumor Dissemination.J Natl Cancer Inst. 2015 Oct 13;108(1):djv289. doi: 10.1093/jnci/djv289. Print 2016 Jan.
• [14] PIG3 plays an oncogenic role in papillary thyroid cancer by activating the PI3K/AKT/PTEN pathway.Oncol Rep. 2015 Sep;34(3):1424-30. doi: 10.3892/or.2015.4096. Epub 2015 Jun 30.
• [15] 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.
• [16] 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.
• [17] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [18] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [19] 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.
• [20] 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.