Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTILGYO4)

• DOT Name: Guanine nucleotide-binding protein-like 3 (GNL3)
• Synonyms: E2-induced gene 3 protein; Novel nucleolar protein 47; NNP47; Nucleolar GTP-binding protein 3; Nucleostemin
• Gene Name: GNL3
• Related Disease:
  T-cell acute lymphoblastic leukaemia
  Acute monocytic leukemia
  Acute myelogenous leukaemia
  Astrocytoma
  Barrett esophagus
  Bladder cancer
  Bone osteosarcoma
  Brain neoplasm
  Breast neoplasm
  Carcinoma of esophagus
  Esophageal squamous cell carcinoma
  Gastric adenocarcinoma
  Gastric cancer
  Gastric neoplasm
  Glioblastoma multiforme
  Hepatocellular carcinoma
  Invasive breast carcinoma
  Knee osteoarthritis
  leukaemia
  Leukemia
  Lung cancer
  Major depressive disorder
  Malignant glioma
  Medulloblastoma
  Neoplasm
  Osteoarthritis
  Osteosarcoma
  Prostate cancer
  Prostate carcinoma
  Schizophrenia
  Sjogren syndrome
  Stomach cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
  Adult lymphoma
  Bipolar disorder
  Cervical carcinoma
  Lung carcinoma
  Lymphoma
  Pediatric lymphoma
  Promyelocytic leukaemia
  Breast cancer
  Breast carcinoma
  Gallbladder cancer
  Gallbladder carcinoma
  Triple negative breast cancer
• UniProt ID: GNL3_HUMAN
• PDB ID: 8FKP; 8FKR; 8FKT; 8FKU; 8FKV; 8FKW; 8FKX; 8FKY; 8FKZ; 8FL0; 8FL2; 8FL3; 8FL4; 8INK; 8IPD; 8IPX; 8IPY; 8IR1; 8IR3
• Pfam ID: PF08701 ; PF01926
• Sequence:
  MKRPKLKKASKRMTCHKRYKIQKKVREHHRKLRKEAKKRGHKKPRKDPGVPNSAPFKEAL
  LREAELRKQRLEELKQQQKLDRQKELEKKRKLETNPDIKPSNVEPMEKEFGLCKTENKAK
  SGKQNSKKLYCQELKKVIEASDVVLEVLDARDPLGCRCPQVEEAIVQSGQKKLVLILNKS
  DLVPKENLESWLNYLKKELPTVVFRASTKPKDKGKITKRVKAKKNAAPFRSEVCFGKEGL
  WKLLGGFQETCSKAIRVGVIGFPNVGKSSIINSLKQEQMCNVGVSMGLTRSMQVVPLDKQ
  ITIIDSPSFIVSPLNSSSALALRSPASIEVVKPMEAASAILSQADARQVVLKYTVPGYRN
  SLEFFTVLAQRRGMHQKGGIPNVEGAAKLLWSEWTGASLAYYCHPPTSWTPPPYFNESIV
  VDMKSGFNLEELEKNNAQSIRAIKGPHLANSILFQSSGLTNGIIEEKDIHEELPKRKERK
  QEEREDDKDSDQETVDEEVDENSSGMFAAEETGEALSEETTAGEQSTRSFILDKIIEEDD
  AYDFSTDYV
• Function: May be required to maintain the proliferative capacity of stem cells. Stabilizes MDM2 by preventing its ubiquitination, and hence proteasomal degradation.
• Tissue Specificity: Increased levels in lung tissue in cancer patients.
• KEGG Pathway: Ribosome biogenesis in eukaryotes (hsa03008)
• Reactome Pathway: Major pathway of rRNA processing in the nucleolus and cytosol (R-HSA-6791226)

Molecular Interaction Atlas (MIA) of This DOT

46 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
T-cell acute lymphoblastic leukaemia	DIS17AI2	Definitive	Biomarker	[1]
Acute monocytic leukemia	DIS28NEL	Strong	Altered Expression	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[3]
Astrocytoma	DISL3V18	Strong	Altered Expression	[4]
Barrett esophagus	DIS416Y7	Strong	Biomarker	[5]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[6]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[7]
Brain neoplasm	DISY3EKS	Strong	Altered Expression	[4]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[8]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[9]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[10]
Gastric adenocarcinoma	DISWWLTC	Strong	Altered Expression	[11]
Gastric cancer	DISXGOUK	Strong	Biomarker	[12]
Gastric neoplasm	DISOKN4Y	Strong	Biomarker	[12]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[13]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[14]
Invasive breast carcinoma	DISANYTW	Strong	Altered Expression	[15]
Knee osteoarthritis	DISLSNBJ	Strong	Biomarker	[16]
leukaemia	DISS7D1V	Strong	Biomarker	[17]
Leukemia	DISNAKFL	Strong	Biomarker	[17]
Lung cancer	DISCM4YA	Strong	Altered Expression	[18]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[19]
Malignant glioma	DISFXKOV	Strong	Altered Expression	[4]
Medulloblastoma	DISZD2ZL	Strong	Altered Expression	[4]
Neoplasm	DISZKGEW	Strong	Altered Expression	[14]
Osteoarthritis	DIS05URM	Strong	Biomarker	[20]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[7]
Prostate cancer	DISF190Y	Strong	Altered Expression	[21]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[21]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[22]
Sjogren syndrome	DISUBX7H	Strong	Altered Expression	[23]
Stomach cancer	DISKIJSX	Strong	Biomarker	[12]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[6]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[6]
Adult lymphoma	DISK8IZR	moderate	Biomarker	[24]
Bipolar disorder	DISAM7J2	moderate	Genetic Variation	[25]
Cervical carcinoma	DIST4S00	moderate	Biomarker	[26]
Lung carcinoma	DISTR26C	moderate	Biomarker	[27]
Lymphoma	DISN6V4S	moderate	Biomarker	[24]
Pediatric lymphoma	DIS51BK2	moderate	Biomarker	[24]
Promyelocytic leukaemia	DISYGG13	moderate	Biomarker	[17]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[15]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[15]
Gallbladder cancer	DISXJUAF	Limited	Altered Expression	[28]
Gallbladder carcinoma	DISD6ACL	Limited	Altered Expression	[28]
Triple negative breast cancer	DISAMG6N	Limited	Altered Expression	[15]

14 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 Guanine nucleotide-binding protein-like 3 (GNL3).	[29]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Guanine nucleotide-binding protein-like 3 (GNL3).	[30]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Guanine nucleotide-binding protein-like 3 (GNL3).	[31]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Guanine nucleotide-binding protein-like 3 (GNL3).	[32]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Guanine nucleotide-binding protein-like 3 (GNL3).	[33]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Guanine nucleotide-binding protein-like 3 (GNL3).	[34]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Guanine nucleotide-binding protein-like 3 (GNL3).	[36]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Guanine nucleotide-binding protein-like 3 (GNL3).	[37]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Guanine nucleotide-binding protein-like 3 (GNL3).	[38]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Guanine nucleotide-binding protein-like 3 (GNL3).	[39]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Guanine nucleotide-binding protein-like 3 (GNL3).	[40]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Guanine nucleotide-binding protein-like 3 (GNL3).	[41]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 decreases the expression of Guanine nucleotide-binding protein-like 3 (GNL3).	[42]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Guanine nucleotide-binding protein-like 3 (GNL3).	[45]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Guanine nucleotide-binding protein-like 3 (GNL3).	[35]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Guanine nucleotide-binding protein-like 3 (GNL3).	[43]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Guanine nucleotide-binding protein-like 3 (GNL3).	[44]

References

• [1] Nucleostemin knocking-down causes cell cycle arrest and apoptosis in human T-cell acute lymphoblastic leukemia MOLT-4 cells via p53 and p21Waf1/Cip1 up-regulation.Hematology. 2014 Dec;19(8):455-62. doi: 10.1179/1607845414Y.0000000153. Epub 2014 Mar 17.
• [2] Transcript level of nucleostemin in newly diagnosed acute myeloid leukemia patients.Leuk Res. 2013 Dec;37(12):1636-41. doi: 10.1016/j.leukres.2013.09.023. Epub 2013 Sep 29.
• [3] Gene expression profiling of HL-60 cells following knockdown of nucleostemin using DNA microarrays.Oncol Rep. 2014 Aug;32(2):739-47. doi: 10.3892/or.2014.3240. Epub 2014 Jun 6.
• [4] Differential expression of nucleostemin, a stem cell marker, and its variants in different types of brain tumors.Mol Carcinog. 2010 Sep;49(9):818-25. doi: 10.1002/mc.20658.
• [5] Inhibition of nucleostemin upregulates CDX2 expression in HT29 cells in response to bile acid exposure: implications in the pathogenesis of Barrett's esophagus.J Gastrointest Surg. 2009 Aug;13(8):1430-9. doi: 10.1007/s11605-009-0899-2. Epub 2009 May 16.
• [6] Differential effects of Nucleostemin suppression on cell cycle arrest and apoptosis in the bladder cancer cell lines 5637 and SW1710.Cell Prolif. 2009 Dec;42(6):762-9. doi: 10.1111/j.1365-2184.2009.00635.x. Epub 2009 Aug 25.
• [7] The oncogenic role of GNL3 in the progression and metastasis of osteosarcoma.Cancer Manag Res. 2019 Mar 15;11:2179-2188. doi: 10.2147/CMAR.S195360. eCollection 2019.
• [8] Nucleostemin reveals a dichotomous nature of genome maintenance in mammary tumor progression.Oncogene. 2019 May;38(20):3919-3931. doi: 10.1038/s41388-019-0710-0. Epub 2019 Jan 28.
• [9] Nucleostemin and TWIST as predictive markers for recurrence after neoadjuvant chemotherapy for esophageal carcinoma.Cancer Sci. 2012 Feb;103(2):233-8. doi: 10.1111/j.1349-7006.2011.02142.x. Epub 2011 Dec 8.
• [10] Expression of nucleostemin, epidermal growth factor and epidermal growth factor receptor in human esophageal squamous cell carcinoma tissues.J Cancer Res Clin Oncol. 2010 Apr;136(4):587-94. doi: 10.1007/s00432-009-0693-2. Epub 2009 Oct 13.
• [11] Concomitant upregulation of nucleostemin and downregulation of Sox2 and Klf4 in gastric adenocarcinoma.Tumour Biol. 2014 Jul;35(7):7177-85. doi: 10.1007/s13277-014-1966-1. Epub 2014 Apr 25.
• [12] Role of nucleostemin in growth regulation of gastric cancer, liver cancer and other malignancies.World J Gastroenterol. 2004 May 1;10(9):1246-9. doi: 10.3748/wjg.v10.i9.1246.
• [13] An off-target nucleostemin RNAi inhibits growth in human glioblastoma-derived cancer stem cells.PLoS One. 2011;6(12):e28753. doi: 10.1371/journal.pone.0028753. Epub 2011 Dec 12.
• [14] Nucleostemin promotes hepatocellular carcinoma by regulating the function of STAT3.Exp Cell Res. 2020 Feb 1;387(1):111748. doi: 10.1016/j.yexcr.2019.111748. Epub 2019 Nov 27.
• [15] Nucleostemin expression in breast cancer is a marker of more aggressive phenotype and unfavorable patients' outcome: A STROBE-compliant article.Medicine (Baltimore). 2019 Mar;98(9):e14744. doi: 10.1097/MD.0000000000014744.
• [16] Common variants in the GNL3 contribute to the increasing risk of knee osteoarthritis in Han Chinese population.Sci Rep. 2018 Jun 25;8(1):9610. doi: 10.1038/s41598-018-27971-4.
• [17] Nucleostemin silencing induces differentiation and potentiates all-trans-retinoic acid effects in human acute promyelocytic leukemia NB4 cells via autophagy.Leuk Res. 2017 Dec;63:15-21. doi: 10.1016/j.leukres.2017.10.007. Epub 2017 Oct 26.
• [18] Cloning of the nucleostemin gene and its function in transforming human embryonic bone marrow mesenchymal stem cells into F6 tumor cells.Int J Mol Med. 2005 Aug;16(2):205-13.
• [19] A mega-analysis of genome-wide association studies for major depressive disorder.Mol Psychiatry. 2013 Apr;18(4):497-511. doi: 10.1038/mp.2012.21. Epub 2012 Apr 3.
• [20] Expression of nucleostemin gene in primary osteoarthritis.Gene. 2016 Aug 1;587(1):27-32. doi: 10.1016/j.gene.2016.04.019. Epub 2016 Apr 9.
• [21] GNL3 and SKA3 are novel prostate cancer metastasis susceptibility genes.Clin Exp Metastasis. 2015 Dec;32(8):769-82. doi: 10.1007/s10585-015-9745-y. Epub 2015 Oct 1.
• [22] The genome-wide risk alleles for psychiatric disorders at 3p21.1 show convergent effects on mRNA expression, cognitive function, and mushroom dendritic spine.Mol Psychiatry. 2020 Jan;25(1):48-66. doi: 10.1038/s41380-019-0592-0. Epub 2019 Nov 13.
• [23] Comparison of telomere length and association with progenitor cell markers in lacrimal gland between Sjgren syndrome and non-Sjgren syndrome dry eye patients.Mol Vis. 2011;17:1397-404. Epub 2011 May 27.
• [24] Suppression of Myc oncogenic activity by nucleostemin haploinsufficiency.Oncogene. 2012 Jul 12;31(28):3311-21. doi: 10.1038/onc.2011.507. Epub 2011 Nov 14.
• [25] Genome-wide association study meta-analysis of European and Asian-ancestry samples identifies three novel loci associated with bipolar disorder.Mol Psychiatry. 2013 Feb;18(2):195-205. doi: 10.1038/mp.2011.157. Epub 2011 Dec 20.
• [26] Stem-cell-abundant proteins Nanog, Nucleostemin and Musashi1 are highly expressed in malignant cervical epithelial cells.BMC Cancer. 2008 Apr 18;8:108. doi: 10.1186/1471-2407-8-108.
• [27] In vitro study of Nucleostemin gene as a potential therapeutic target for human lung carcinoma.Biomed Environ Sci. 2012 Feb;25(1):91-7. doi: 10.3967/0895-3988.2012.01.013.
• [28] Significance of epithelial growth factor in the epithelial-mesenchymal transition of human gallbladder cancer cells.Cancer Sci. 2012 Jun;103(6):1165-71. doi: 10.1111/j.1349-7006.2012.02264.x. Epub 2012 Apr 3.
• [29] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [30] 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.
• [31] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [32] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [33] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [34] 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.
• [35] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [36] 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.
• [37] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [38] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [39] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [40] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [41] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [42] OTX015 Epi-Drug Exerts Antitumor Effects in Ovarian Cancer Cells by Blocking GNL3-Mediated Radioresistance Mechanisms: Cellular, Molecular and Computational Evidence. Cancers (Basel). 2021 Mar 25;13(7):1519. doi: 10.3390/cancers13071519.
• [43] 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.
• [44] 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.
• [45] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.