Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1HXEPM)

• DOT Name: GRAM domain-containing protein 4 (GRAMD4)
• Synonyms: Death-inducing protein
• Gene Name: GRAMD4
• Related Disease:
  Alzheimer disease
  Lung squamous cell carcinoma
  Acute myelogenous leukaemia
• UniProt ID: GRAM4_HUMAN
• Pfam ID: PF02893
• Sequence:
  MLRRLDKIRFRGHKRDDFLDLAESPNASDTECSDEIPLKVPRTSPRDSEELRDPAGPGTL
  IMATGVQDFNRTEFDRLNEIKGHLEIALLEKHFLQEELRKLREETNAEMLRQELDRERQR
  RMELEQKVQEVLKARTEEQMAQQPPKGQAQASNGAERRSQGLSSRLQKWFYERFGEYVED
  FRFQPEENTVETEEPLSARRLTENMRRLKRGAKPVTNFVKNLSALSDWYSVYTSAIAFTV
  YMNAVWHGWAIPLFLFLAILRLSLNYLIARGWRIQWSIVPEVSEPVEPPKEDLTVSEKFQ
  LVLDVAQKAQNLFGKMADILEKIKNLFMWVQPEITQKLYVALWAAFLASCFFPYRLVGLA
  VGLYAGIKFFLIDFIFKRCPRLRAKYDTPYIIWRSLPTDPQLKERSSAAVSRRLQTTSSR
  SYVPSAPAGLGKEEDAGRFHSTKKGNFHEIFNLTENERPLAVCENGWRCCLINRDRKMPT
  DYIRNGVLYVTENYLCFESSKSGSSKRNKVIKLVDITDIQKYKVLSVLPGSGMGIAVSTP
  STQKPLVFGAMVHRDEAFETILSQYIKITSAAASGGDS
• Function: Plays a role as a mediator of E2F1-induced apoptosis in the absence of p53/TP53. Plays a role as a mediator of E2F1-induced apoptosis in the absence of p53/TP53. Inhibits TLR9 response to nucelic acids and regulates TLR9-mediated innate immune response.
• Tissue Specificity: Expressed in lung and in primary lung squamous cell carcinoma (LSCC).

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
Lung squamous cell carcinoma	DISXPIBD	Strong	Altered Expression	[2]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[3]

3 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 GRAM domain-containing protein 4 (GRAMD4).	[4]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of GRAM domain-containing protein 4 (GRAMD4).	[7]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of GRAM domain-containing protein 4 (GRAMD4).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of GRAM domain-containing protein 4 (GRAMD4).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of GRAM domain-containing protein 4 (GRAMD4).	[6]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of GRAM domain-containing protein 4 (GRAMD4).	[8]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of GRAM domain-containing protein 4 (GRAMD4).	[9]
Malathion	DMXZ84M	Approved	Malathion decreases the expression of GRAM domain-containing protein 4 (GRAMD4).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of GRAM domain-containing protein 4 (GRAMD4).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of GRAM domain-containing protein 4 (GRAMD4).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of GRAM domain-containing protein 4 (GRAMD4).	[14]

References

• [1] Amyloid beta protein-related death-inducing protein induces G2/M arrest: Implications for neurodegeneration in Alzheimer's disease. J Neurosci Res. 2007 Aug 1;85(10):2262-71. doi: 10.1002/jnr.21351.
• [2] Molecular profiling of genes in squamous cell lung carcinoma in Asian Indians.Life Sci. 2008 Mar 26;82(13-14):772-9. doi: 10.1016/j.lfs.2008.01.009. Epub 2008 Jan 30.
• [3] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [4] 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.
• [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] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [7] 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.
• [8] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [9] GRAMD4 mimics p53 and mediates the apoptotic function of p73 at mitochondria. Cell Death Differ. 2011 May;18(5):874-86. doi: 10.1038/cdd.2010.153. Epub 2010 Dec 3.
• [10] 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.
• [11] Malathion induced cancer-linked gene expression in human lymphocytes. Environ Res. 2020 Mar;182:109131. doi: 10.1016/j.envres.2020.109131. Epub 2020 Jan 10.
• [12] 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.
• [13] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [14] 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.