Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCK4IGV)

• DOT Name: Gremlin-1 (GREM1)
• Synonyms: Cell proliferation-inducing gene 2 protein; Cysteine knot superfamily 1, BMP antagonist 1; DAN domain family member 2; Down-regulated in Mos-transformed cells protein; Increased in high glucose protein 2; IHG-2
• Gene Name: GREM1
• Related Disease:
  Hereditary mixed polyposis syndrome
  Polyposis syndrome, hereditary mixed, 1
• UniProt ID: GREM1_HUMAN
• PDB ID: 5AEJ
• Pfam ID: PF03045
• Sequence:
  MSRTAYTVGALLLLLGTLLPAAEGKKKGSQGAIPPPDKAQHNDSEQTQSPQQPGSRNRGR
  GQGRGTAMPGEEVLESSQEALHVTERKYLKRDWCKTQPLKQTIHEEGCNSRTIINRFCYG
  QCNSFYIPRHIRKEEGSFQSCSFCKPKKFTTMMVTLNCPELQPPTKKKRVTRVKQCRCIS
  IDLD
• Function: Cytokine that may play an important role during carcinogenesis and metanephric kidney organogenesis, as a BMP antagonist required for early limb outgrowth and patterning in maintaining the FGF4-SHH feedback loop. Down-regulates the BMP4 signaling in a dose-dependent manner. Antagonist of BMP2; inhibits BMP2-mediated differentiation of osteoblasts (in vitro). Acts as inhibitor of monocyte chemotaxis. Can inhibit the growth or viability of normal cells but not transformed cells when is overexpressed.
• Tissue Specificity: Highly expressed in small intestine, fetal brain and colon. Expression is restricted to intestinal subepithelial myofibroblasts (ISEMFs) at the crypt base. In subjects with HMPS1, by contrast, GREM1 is expressed, not only in basal ISEMFs, but also at very high levels in epithelial cells (predominantly colonocytes), with expression extending most of the way up the sides of the crypt. Weakly expressed in brain, ovary, prostate, pancreas and skeletal muscle. In brain found in the region localized around the internal capsule in the large subcortical nuclei, including caudate, putamen, substantia nigra, thalamus and subthalamus. Predominantly expressed in normal cells including neurons, astrocytes and fibroblasts.
• KEGG Pathway: TGF-beta sig.ling pathway (hsa04350)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hereditary mixed polyposis syndrome	DISPNBY1	Definitive	Autosomal dominant	[1]
Polyposis syndrome, hereditary mixed, 1	DISG6RBU	Strong	Autosomal dominant	[2]

26 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 Gremlin-1 (GREM1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Gremlin-1 (GREM1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Gremlin-1 (GREM1).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Gremlin-1 (GREM1).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Gremlin-1 (GREM1).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Gremlin-1 (GREM1).	[8]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Gremlin-1 (GREM1).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Gremlin-1 (GREM1).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Gremlin-1 (GREM1).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Gremlin-1 (GREM1).	[12]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Gremlin-1 (GREM1).	[13]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Gremlin-1 (GREM1).	[14]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Gremlin-1 (GREM1).	[15]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Gremlin-1 (GREM1).	[16]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Gremlin-1 (GREM1).	[14]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Gremlin-1 (GREM1).	[17]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Gremlin-1 (GREM1).	[14]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Gremlin-1 (GREM1).	[14]
DNCB	DMDTVYC	Phase 2	DNCB increases the expression of Gremlin-1 (GREM1).	[18]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Gremlin-1 (GREM1).	[20]
SB-431542	DM0YOXQ	Preclinical	SB-431542 decreases the expression of Gremlin-1 (GREM1).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Gremlin-1 (GREM1).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Gremlin-1 (GREM1).	[23]
D-glucose	DMMG2TO	Investigative	D-glucose increases the expression of Gremlin-1 (GREM1).	[24]
Nitrobenzanthrone	DMN6L70	Investigative	Nitrobenzanthrone increases the expression of Gremlin-1 (GREM1).	[25]
Lead acetate	DML0GZ2	Investigative	Lead acetate increases the expression of Gremlin-1 (GREM1).	[26]

1 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 decreases the methylation of Gremlin-1 (GREM1).	[19]

References

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• [2] Hereditary mixed polyposis syndrome is caused by a 40-kb upstream duplication that leads to increased and ectopic expression of the BMP antagonist GREM1. Nat Genet. 2012 May 6;44(6):699-703. doi: 10.1038/ng.2263.
• [3] 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.
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• [14] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [15] Chemical genomic screening for methylation-silenced genes in gastric cancer cell lines using 5-aza-2'-deoxycytidine treatment and oligonucleotide microarray. Cancer Sci. 2006 Jan;97(1):64-71.
• [16] Progesterone regulation of implantation-related genes: new insights into the role of oestrogen. Cell Mol Life Sci. 2007 Apr;64(7-8):1009-32.
• [17] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [18] Upregulation of genes orchestrating keratinocyte differentiation, including the novel marker gene ID2, by contact sensitizers in human bulge-derived keratinocytes. J Biochem Mol Toxicol. 2010 Jan-Feb;24(1):10-20.
• [19] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [20] Synergistic effect of JQ1 and rapamycin for treatment of human osteosarcoma. Int J Cancer. 2015 May 1;136(9):2055-64.
• [21] Gremlin-mediated decrease in bone morphogenetic protein signaling promotes pulmonary fibrosis. Am J Respir Crit Care Med. 2008 Feb 1;177(3):321-9. doi: 10.1164/rccm.200706-945OC. Epub 2007 Nov 1.
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• [23] 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.
• [24] Suppression subtractive hybridization identifies high glucose levels as a stimulus for expression of connective tissue growth factor and other genes in human mesangial cells. J Biol Chem. 1999 Feb 26;274(9):5830-4. doi: 10.1074/jbc.274.9.5830.
• [25] 3-Nitrobenzanthrone promotes malignant transformation in human lung epithelial cells through the epiregulin-signaling pathway. Cell Biol Toxicol. 2022 Oct;38(5):865-887. doi: 10.1007/s10565-021-09612-1. Epub 2021 May 25.
• [26] In vitro effects of lead on gene expression in neural stem cells and associations between up-regulated genes and cognitive scores in children. Environ Health Perspect. 2017 Apr;125(4):721-729.