Details of Drug Off-Target (DOT)

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

• DOT Name: Large ribosomal subunit protein uL16 (RPL10)
• Synonyms: 60S ribosomal protein L10; Laminin receptor homolog; Protein QM; Ribosomal protein L10; Tumor suppressor QM
• Gene Name: RPL10
• Related Disease:
  Intellectual disability, X-linked, syndromic, 35
  Wilms tumor
  Advanced cancer
  Autism
  Autism spectrum disorder
  B-cell neoplasm
  Benign prostatic hyperplasia
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Epilepsy
  Epithelial ovarian cancer
  Gastric cancer
  Hepatocellular carcinoma
  Intellectual disability
  Intervertebral disc degeneration
  Isolated congenital microcephaly
  Male infertility
  Neoplasm
  Nephropathy
  Neurodevelopmental disorder
  Obesity
  Prostate adenocarcinoma
  Prostate neoplasm
  Small lymphocytic lymphoma
  Stomach cancer
  T-cell acute lymphoblastic leukaemia
  T-cell leukaemia
  Type-1/2 diabetes
  Urinary bladder cancer
  Urinary bladder neoplasm
  Bone osteosarcoma
  Colorectal carcinoma
  Metastatic malignant neoplasm
  Osteosarcoma
  X-linked syndromic intellectual disability
  X-linked intellectual disability-cerebellar hypoplasia-spondylo-epiphyseal dysplasia syndrome
  X-linked microcephaly-growth retardation-prognathism-cryptorchidism syndrome
  Adenocarcinoma
  Autism, susceptibility to, X-linked 5
  Childhood kidney Wilms tumor
  Endometrial cancer
  Endometrial carcinoma
  Female hypogonadism
  Hyperglycemia
  Hyperlipidemia
  Pancreatic cancer
  Partington syndrome
  Prostate cancer
  Prostate carcinoma
• UniProt ID: RL10_HUMAN
• PDB ID: 2PA2; 5AJ0; 6OLE; 6OLF; 6OLG; 6OLI; 6OLZ; 6OM0; 6OM7; 6W6L; 7F5S; 8A3D; 8FLD; 8FLE; 8FLF; 8G5Y; 8G5Z; 8G60; 8G61; 8G6J; 8GLP
• Pfam ID: PF00252
• Sequence:
  MGRRPARCYRYCKNKPYPKSRFCRGVPDAKIRIFDLGRKKAKVDEFPLCGHMVSDEYEQL
  SSEALEAARICANKYMVKSCGKDGFHIRVRLHPFHVIRINKMLSCAGADRLQTGMRGAFG
  KPQGTVARVHIGQVIMSIRTKLQNKEHVIEALRRAKFKFPGRQKIHISKKWGFTKFNADE
  FEDMVAEKRLIPDGCGVKYIPSRGPLDKWRALHS
• Function: Component of the large ribosomal subunit. Plays a role in the formation of actively translating ribosomes. May play a role in the embryonic brain development.
• KEGG Pathway:
  Ribosome (hsa03010)
  Coro.virus disease - COVID-19 (hsa05171)
• Reactome Pathway:
  Peptide chain elongation (R-HSA-156902)
  SRP-dependent cotranslational protein targeting to membrane (R-HSA-1799339)
  Viral mRNA Translation (R-HSA-192823)
  Selenocysteine synthesis (R-HSA-2408557)
  Major pathway of rRNA processing in the nucleolus and cytosol (R-HSA-6791226)
  Formation of a pool of free 40S subunits (R-HSA-72689)
  GTP hydrolysis and joining of the 60S ribosomal subunit (R-HSA-72706)
  Eukaryotic Translation Termination (R-HSA-72764)
  Regulation of expression of SLITs and ROBOs (R-HSA-9010553)
  Response of EIF2AK4 (GCN2) to amino acid deficiency (R-HSA-9633012)
  Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC) (R-HSA-975956)
  Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) (R-HSA-975957)
  L13a-mediated translational silencing of Ceruloplasmin expression (R-HSA-156827)

Molecular Interaction Atlas (MIA) of This DOT

50 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability, X-linked, syndromic, 35	DISAYIBV	Definitive	X-linked	[1]
Wilms tumor	DISB6T16	Definitive	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Autism	DISV4V1Z	Strong	Genetic Variation	[4]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[5]
B-cell neoplasm	DISVY326	Strong	Genetic Variation	[6]
Benign prostatic hyperplasia	DISI3CW2	Strong	Biomarker	[7]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[8]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[8]
Epilepsy	DISBB28L	Strong	Genetic Variation	[9]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[2]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[10]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[11]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[9]
Intervertebral disc degeneration	DISG3AIM	Strong	Biomarker	[12]
Isolated congenital microcephaly	DISUXHZ6	Strong	Biomarker	[5]
Male infertility	DISY3YZZ	Strong	Altered Expression	[13]
Neoplasm	DISZKGEW	Strong	Biomarker	[14]
Nephropathy	DISXWP4P	Strong	Biomarker	[15]
Neurodevelopmental disorder	DIS372XH	Strong	Genetic Variation	[4]
Obesity	DIS47Y1K	Strong	Biomarker	[16]
Prostate adenocarcinoma	DISBZYU8	Strong	Altered Expression	[7]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[17]
Small lymphocytic lymphoma	DIS30POX	Strong	Genetic Variation	[18]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[10]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Strong	Genetic Variation	[18]
T-cell leukaemia	DISJ6YIF	Strong	Genetic Variation	[19]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[16]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[3]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[3]
Bone osteosarcoma	DIST1004	moderate	Biomarker	[20]
Colorectal carcinoma	DIS5PYL0	moderate	Biomarker	[21]
Metastatic malignant neoplasm	DIS86UK6	moderate	Altered Expression	[21]
Osteosarcoma	DISLQ7E2	moderate	Biomarker	[20]
X-linked syndromic intellectual disability	DISG1YOH	Moderate	X-linked	[22]
X-linked intellectual disability-cerebellar hypoplasia-spondylo-epiphyseal dysplasia syndrome	DIS8728Z	Supportive	X-linked	[1]
X-linked microcephaly-growth retardation-prognathism-cryptorchidism syndrome	DIS9GQYY	Supportive	X-linked	[5]
Adenocarcinoma	DIS3IHTY	Limited	Altered Expression	[23]
Autism, susceptibility to, X-linked 5	DISRWVO4	Limited	X-linked	[24]
Childhood kidney Wilms tumor	DIS0NMK3	Limited	Biomarker	[2]
Endometrial cancer	DISW0LMR	Limited	Genetic Variation	[25]
Endometrial carcinoma	DISXR5CY	Limited	Genetic Variation	[25]
Female hypogonadism	DISWASB4	Limited	Biomarker	[2]
Hyperglycemia	DIS0BZB5	Limited	Altered Expression	[26]
Hyperlipidemia	DIS61J3S	Limited	Altered Expression	[26]
Pancreatic cancer	DISJC981	Limited	Biomarker	[27]
Partington syndrome	DIS3H205	Limited	Biomarker	[9]
Prostate cancer	DISF190Y	Limited	Altered Expression	[28]
Prostate carcinoma	DISMJPLE	Limited	Altered Expression	[28]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Paclitaxel	DMLB81S	Approved	Large ribosomal subunit protein uL16 (RPL10) affects the response to substance of Paclitaxel.	[40]

8 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 Large ribosomal subunit protein uL16 (RPL10).	[29]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Large ribosomal subunit protein uL16 (RPL10).	[30]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Large ribosomal subunit protein uL16 (RPL10).	[31]
Ursodeoxycholic acid	DMCUT21	Approved	Ursodeoxycholic acid affects the expression of Large ribosomal subunit protein uL16 (RPL10).	[32]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Large ribosomal subunit protein uL16 (RPL10).	[34]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Large ribosomal subunit protein uL16 (RPL10).	[35]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Large ribosomal subunit protein uL16 (RPL10).	[38]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of Large ribosomal subunit protein uL16 (RPL10).	[39]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Dihydroartemisinin	DMBXVMZ	Approved	Dihydroartemisinin affects the binding of Large ribosomal subunit protein uL16 (RPL10).	[33]

2 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 affects the methylation of Large ribosomal subunit protein uL16 (RPL10).	[36]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Large ribosomal subunit protein uL16 (RPL10).	[37]

References

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• [2] Biological Function of Ribosomal Protein L10 on Cell Behavior in Human Epithelial Ovarian Cancer.J Cancer. 2018 Feb 6;9(4):745-756. doi: 10.7150/jca.21614. eCollection 2018.
• [3] NOV is upregulated and promotes migration and invasion in bladder cancer.Tumour Biol. 2014 Jul;35(7):6749-55. doi: 10.1007/s13277-014-1919-8. Epub 2014 Apr 10.
• [4] RPL10 mutation segregating in a family with X-linked syndromic Intellectual Disability.Am J Med Genet A. 2015 Aug;167A(8):1908-12. doi: 10.1002/ajmg.a.37094. Epub 2015 Apr 6.
• [5] A novel ribosomopathy caused by dysfunction of RPL10 disrupts neurodevelopment and causes X-linked microcephaly in humans. Genetics. 2014 Oct;198(2):723-33. doi: 10.1534/genetics.114.168211.
• [6] The ribosomal RPL10 R98S mutation drives IRES-dependent BCL-2 translation in T-ALL.Leukemia. 2019 Feb;33(2):319-332. doi: 10.1038/s41375-018-0176-z. Epub 2018 Jun 21.
• [7] Differential expression of the ccn3 (nov) proto-oncogene in human prostate cell lines and tissues.Mol Pathol. 2001 Aug;54(4):275-80. doi: 10.1136/mp.54.4.275.
• [8] Osteoblasts are "educated" by crosstalk with metastatic breast cancer cells in the bone tumor microenvironment.Breast Cancer Res. 2019 Feb 27;21(1):31. doi: 10.1186/s13058-019-1117-0.
• [9] A de novo mutation in RPL10 causes a rare X-linked ribosomopathy characterized by syndromic intellectual disability and epilepsy: A new case and review of the literature.Eur J Med Genet. 2018 Feb;61(2):89-93. doi: 10.1016/j.ejmg.2017.10.011. Epub 2017 Oct 21.
• [10] Differential expression of CCN family members CYR611, CTGF and NOV in gastric cancer and their association with disease progression.Oncol Rep. 2016 Nov;36(5):2517-2525. doi: 10.3892/or.2016.5074. Epub 2016 Sep 8.
• [11] Expressions of cysteine-rich61, connective tissue growth factor and Nov genes in hepatocellular carcinoma and their clinical significance.World J Gastroenterol. 2004 Dec 1;10(23):3414-8. doi: 10.3748/wjg.v10.i23.3414.
• [12] Bioinformatics analysis of the gene expression profiles in human intervertebral disc degeneration associated with inflammatory cytokines.J Neurosurg Sci. 2018 Feb;62(1):16-23. doi: 10.23736/S0390-5616.16.03326-9. Epub 2015 Jul 22.
• [13] RPL10L Is Required for Male Meiotic Division by Compensating for RPL10 during Meiotic Sex Chromosome Inactivation in Mice.Curr Biol. 2017 May 22;27(10):1498-1505.e6. doi: 10.1016/j.cub.2017.04.017. Epub 2017 May 11.
• [14] Imatinib independent aberrant methylation of NOV/CCN3 in chronic myelogenous leukemia patients: a mechanism upstream of BCR-ABL1 function?.Cell Commun Signal. 2019 Apr 23;17(1):38. doi: 10.1186/s12964-019-0350-6.
• [15] Reduced NOV/CCN3 Expression Limits Inflammation and Interstitial Renal Fibrosis after Obstructive Nephropathy in Mice.PLoS One. 2015 Sep 14;10(9):e0137876. doi: 10.1371/journal.pone.0137876. eCollection 2015.
• [16] Role of Omentin, Vaspin, Cardiotrophin-1, TWEAK and NOV/CCN3 in Obesity and Diabetes Development.Int J Mol Sci. 2017 Aug 15;18(8):1770. doi: 10.3390/ijms18081770.
• [17] Identification of genes potentially involved in the acquisition of androgen-independent and metastatic tumor growth in an autochthonous genetically engineered mouse prostate cancer model.Prostate. 2007 Jan 1;67(1):83-106. doi: 10.1002/pros.20505.
• [18] Ribosomal Lesions Promote Oncogenic Mutagenesis.Cancer Res. 2019 Jan 15;79(2):320-327. doi: 10.1158/0008-5472.CAN-18-1987. Epub 2018 Nov 27.
• [19] The T-cell leukemia-associated ribosomal RPL10 R98S mutation enhances JAK-STAT signaling.Leukemia. 2018 Mar;32(3):809-819. doi: 10.1038/leu.2017.225. Epub 2017 Jul 24.
• [20] NOV inhibits proliferation while promoting apoptosis and migration in osteosarcoma cell lines through p38/MAPK and JNK/MAPK pathways.Oncol Rep. 2015 Oct;34(4):2011-21. doi: 10.3892/or.2015.4153. Epub 2015 Jul 24.
• [21] Reduced NOV expression correlates with disease progression in colorectal cancer and is associated with survival, invasion and chemoresistance of cancer cells.Oncotarget. 2017 Apr 18;8(16):26231-26244. doi: 10.18632/oncotarget.15439.
• [22] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [23] Reduction of QM protein expression correlates with tumor grade in prostatic adenocarcinoma.Prostate Cancer Prostatic Dis. 2006;9(1):77-82. doi: 10.1038/sj.pcan.4500848.
• [24] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [25] Role of ribosomal protein mutations in tumor development (Review).Int J Oncol. 2016 Apr;48(4):1313-24. doi: 10.3892/ijo.2016.3387. Epub 2016 Feb 9.
• [26] Eyeing the Cyr61/CTGF/NOV (CCN) group of genes in development and diseases: highlights of their structural likenesses and functional dissimilarities.Hum Genomics. 2015 Sep 23;9:24. doi: 10.1186/s40246-015-0046-y.
• [27] Ribosomal protein L10 in mitochondria serves as a regulator for ROS level in pancreatic cancer cells.Redox Biol. 2018 Oct;19:158-165. doi: 10.1016/j.redox.2018.08.016. Epub 2018 Aug 24.
• [28] CCN3/NOV gene expression in human prostate cancer is directly suppressed by the androgen receptor.Oncogene. 2014 Jan 23;33(4):504-13. doi: 10.1038/onc.2012.602. Epub 2013 Jan 14.
• [29] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [30] Identification of estrogen-induced genes downregulated by AhR agonists in MCF-7 breast cancer cells using suppression subtractive hybridization. Gene. 2001 Jan 10;262(1-2):207-14. doi: 10.1016/s0378-1119(00)00530-8.
• [31] 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.
• [32] Gene expression profiling of early primary biliary cirrhosis: possible insights into the mechanism of action of ursodeoxycholic acid. Liver Int. 2008 Aug;28(7):997-1010. doi: 10.1111/j.1478-3231.2008.01744.x. Epub 2008 Apr 15.
• [33] Untargeted Proteomics and Systems-Based Mechanistic Investigation of Artesunate in Human Bronchial Epithelial Cells. Chem Res Toxicol. 2015 Oct 19;28(10):1903-13. doi: 10.1021/acs.chemrestox.5b00105. Epub 2015 Sep 21.
• [34] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [35] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [36] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [37] 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.
• [38] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [39] ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis. Blood. 2004 Jan 1;103(1):194-207.
• [40] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.