Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCG1GX2)

• DOT Name: Protein Aster-B (GRAMD1B)
• Synonyms: GRAM domain-containing protein 1B
• Gene Name: GRAMD1B
• Related Disease:
  Small lymphocytic lymphoma
  Breast cancer
  Breast carcinoma
  Classic Hodgkin lymphoma
  Erectile dysfunction
  Follicular lymphoma
  Nasopharyngeal carcinoma
  Neoplasm of mature B-cells
  Plasma cell myeloma
  Schizophrenia
  Bipolar disorder
  Gastric cancer
  Neoplasm
  Stomach cancer
• UniProt ID: ASTRB_HUMAN
• Pfam ID: PF02893 ; PF16016
• Sequence:
  MKGFKLSCTASNSNRSTPACSPILRKRSRSPTPQNQDGDTMVEKGSDHSSDKSPSTPEQG
  VQRSCSSQSGRSGGKNSKKSQSWYNVLSPTYKQRNEDFRKLFKQLPDTERLIVDYSCALQ
  RDILLQGRLYLSENWICFYSNIFRWETLLTVRLKDICSMTKEKTARLIPNAIQVCTDSEK
  HFFTSFGARDRTYMMMFRLWQNALLEKPLCPKELWHFVHQCYGNELGLTSDDEDYVPPDD
  DFNTMGYCEEIPVEENEVNDSSSKSSIETKPDASPQLPKKSITNSTLTSTGSSEAPVSFD
  GLPLEEEALEGDGSLEKELAIDNIMGEKIEMIAPVNSPSLDFNDNEDIPTELSDSSDTHD
  EGEVQAFYEDLSGRQYVNEVFNFSVDKLYDLLFTNSPFQRDFMEQRRFSDIIFHPWKKEE
  NGNQSRVILYTITLTNPLAPKTATVRETQTMYKASQESECYVIDAEVLTHDVPYHDYFYT
  INRYTLTRVARNKSRLRVSTELRYRKQPWGLVKTFIEKNFWSGLEDYFRHLESELAKTES
  TYLAEMHRQSPKEKASKTTTVRRRKRPHAHLRVPHLEEVMSPVTTPTDEDVGHRIKHVAG
  STQTRHIPEDTPNGFHLQSVSKLLLVISCVICFSLVLLVILNMMLFYKLWMLEYTTQTLT
  AWQGLRLQERLPQSQTEWAQLLESQQKYHDTELQKWREIIKSSVMLLDQMKDSLINLQNG
  IRSRDYTSESEEKRNRYH
• Function: Cholesterol transporter that mediates non-vesicular transport of cholesterol from the plasma membrane (PM) to the endoplasmic reticulum (ER). Contains unique domains for binding cholesterol and the PM, thereby serving as a molecular bridge for the transfer of cholesterol from the PM to the ER. Plays a crucial role in cholesterol homeostasis in the adrenal gland and has the unique ability to localize to the PM based on the level of membrane cholesterol. In lipid-poor conditions localizes to the ER membrane and in response to excess cholesterol in the PM is recruited to the endoplasmic reticulum-plasma membrane contact sites (EPCS) which is mediated by the GRAM domain. At the EPCS, the sterol-binding VASt/ASTER domain binds to the cholesterol in the PM and facilitates its transfer from the PM to ER.

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Small lymphocytic lymphoma	DIS30POX	Definitive	Genetic Variation	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Genetic Variation	[3]
Erectile dysfunction	DISD8MTH	Strong	Genetic Variation	[4]
Follicular lymphoma	DISVEUR6	Strong	Genetic Variation	[5]
Nasopharyngeal carcinoma	DISAOTQ0	Strong	Genetic Variation	[6]
Neoplasm of mature B-cells	DISKAXO0	Strong	Genetic Variation	[5]
Plasma cell myeloma	DIS0DFZ0	Strong	Genetic Variation	[3]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[7]
Bipolar disorder	DISAM7J2	moderate	Genetic Variation	[8]
Gastric cancer	DISXGOUK	moderate	Altered Expression	[9]
Neoplasm	DISZKGEW	moderate	Altered Expression	[9]
Stomach cancer	DISKIJSX	moderate	Altered Expression	[9]

11 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 Protein Aster-B (GRAMD1B).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Protein Aster-B (GRAMD1B).	[11]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Protein Aster-B (GRAMD1B).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein Aster-B (GRAMD1B).	[13]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Protein Aster-B (GRAMD1B).	[14]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Protein Aster-B (GRAMD1B).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Protein Aster-B (GRAMD1B).	[17]
Mivebresib	DMCPF90	Phase 1	Mivebresib decreases the expression of Protein Aster-B (GRAMD1B).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protein Aster-B (GRAMD1B).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Protein Aster-B (GRAMD1B).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Protein Aster-B (GRAMD1B).	[21]

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 Protein Aster-B (GRAMD1B).	[16]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Protein Aster-B (GRAMD1B).	[22]

References

• [1] Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia.Nat Commun. 2017 Feb 6;8:14175. doi: 10.1038/ncomms14175.
• [2] GRAMD1B regulates cell migration in breast cancer cells through JAK/STAT and Akt signaling.Sci Rep. 2018 Jun 22;8(1):9511. doi: 10.1038/s41598-018-27864-6.
• [3] Genome-wide association analysis of chronic lymphocytic leukaemia, Hodgkin lymphoma and multiple myeloma identifies pleiotropic risk loci.Sci Rep. 2017 Jan 23;7:41071. doi: 10.1038/srep41071.
• [4] Pilot genome-wide association search identifies potential loci for risk of erectile dysfunction in type 1 diabetes using the DCCT/EDIC study cohort.J Urol. 2012 Aug;188(2):514-20. doi: 10.1016/j.juro.2012.04.001. Epub 2012 Jun 15.
• [5] Genome-wide association study of follicular lymphoma identifies a risk locus at 6p21.32.Nat Genet. 2010 Aug;42(8):661-4. doi: 10.1038/ng.626. Epub 2010 Jul 18.
• [6] A genome-wide association study of nasopharyngeal carcinoma identifies three new susceptibility loci.Nat Genet. 2010 Jul;42(7):599-603. doi: 10.1038/ng.601. Epub 2010 May 30.
• [7] Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect.Schizophr Bull. 2019 Jun 18;45(4):824-834. doi: 10.1093/schbul/sby140.
• [8] Association of Polygenic Score for Schizophrenia and HLA Antigen and Inflammation Genes With Response to Lithium in Bipolar Affective Disorder: A Genome-Wide Association Study.JAMA Psychiatry. 2018 Jan 1;75(1):65-74. doi: 10.1001/jamapsychiatry.2017.3433.
• [9] GRAM domain-containing protein 1B (GRAMD1B), a novel component of the JAK/STAT signaling pathway, functions in gastric carcinogenesis.Oncotarget. 2017 Dec 15;8(70):115370-115383. doi: 10.18632/oncotarget.23265. eCollection 2017 Dec 29.
• [10] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [11] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [12] 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.
• [13] 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.
• [14] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [15] Characterizing the genetic basis for nicotine induced cancer development: a transcriptome sequencing study. PLoS One. 2013 Jun 18;8(6):e67252.
• [16] 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.
• [17] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [18] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [19] 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.
• [20] 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.
• [21] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [22] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.