Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT536XAV)

• DOT Name: ADP-ribosylation factor-like protein 6-interacting protein 1 (ARL6IP1)
• Synonyms: ARL-6-interacting protein 1; Aip-1; Apoptotic regulator in the membrane of the endoplasmic reticulum
• Gene Name: ARL6IP1
• Related Disease:
  Cervical cancer
  Cervical carcinoma
  Hereditary spastic paraplegia
  Amyloidosis
  Cardiovascular disease
  Channelopathy-associated congenital insensitivity to pain, autosomal recessive
  Cholangiocarcinoma
  Colorectal carcinoma
  Complex hereditary spastic paraplegia
  Esophageal squamous cell carcinoma
  Hereditary sensory and autonomic neuropathy
  Hereditary spastic paraplegia 61
  Inflammatory bowel disease
  Lung cancer
  Lung carcinoma
  Ocular melanoma
  Prostate cancer
  Prostate neoplasm
  Vascular purpura
  Atherosclerosis
  Breast cancer
  Breast carcinoma
  Melanoma
  Arteriosclerosis
• UniProt ID: AR6P1_HUMAN
• Sequence:
  MAEGDNRSTNLLAAETASLEEQLQGWGEVMLMADKVLRWERAWFPPAIMGVVSLVFLIIY
  YLDPSVLSGVSCFVMFLCLADYLVPILAPRIFGSNKWTTEQQQRFHEICSNLVKTRRRAV
  GWWKRLFTLKEEKPKMYFMTMIVSLAAVAWVGQQVHNLLLTYLIVTSLLLLPGLNQHGII
  LKYIGMAKREINKLLKQKEKKNE
• Function: Positively regulates SLC1A1/EAAC1-mediated glutamate transport by increasing its affinity for glutamate in a PKC activity-dependent manner. Promotes the catalytic efficiency of SLC1A1/EAAC1 probably by reducing its interaction with ARL6IP5, a negative regulator of SLC1A1/EAAC1-mediated glutamate transport. Plays a role in the formation and stabilization of endoplasmic reticulum tubules. Negatively regulates apoptosis, possibly by modulating the activity of caspase-9 (CASP9). Inhibits cleavage of CASP9-dependent substrates and downstream markers of apoptosis but not CASP9 itself. May be involved in protein transport, membrane trafficking, or cell signaling during hematopoietic maturation.
• Tissue Specificity: Expressed in all hematopoietic cell lineages, but the highest level of expression is found in early myeloid progenitor cells. Expressed in brain, bone marrow, thymus and lung. Expressed at low level in liver, kidney and spleen. Not detected in heart.

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cervical cancer	DISFSHPF	Definitive	Biomarker	[1]
Cervical carcinoma	DIST4S00	Definitive	Biomarker	[1]
Hereditary spastic paraplegia	DISGZQV1	Definitive	Autosomal recessive	[2]
Amyloidosis	DISHTAI2	Strong	Genetic Variation	[3]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[4]
Channelopathy-associated congenital insensitivity to pain, autosomal recessive	DISJ1NV4	Strong	Genetic Variation	[5]
Cholangiocarcinoma	DIS71F6X	Strong	Biomarker	[6]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[7]
Complex hereditary spastic paraplegia	DIS9KXQY	Strong	Genetic Variation	[8]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[9]
Hereditary sensory and autonomic neuropathy	DIS2VOAM	Strong	Biomarker	[5]
Hereditary spastic paraplegia 61	DIS2JHPC	Strong	Autosomal recessive	[10]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[7]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[11]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[11]
Ocular melanoma	DISOHHFC	Strong	Biomarker	[12]
Prostate cancer	DISF190Y	Strong	Biomarker	[13]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[13]
Vascular purpura	DIS6ZZMF	Strong	Genetic Variation	[8]
Atherosclerosis	DISMN9J3	moderate	Altered Expression	[14]
Breast cancer	DIS7DPX1	moderate	Genetic Variation	[15]
Breast carcinoma	DIS2UE88	moderate	Genetic Variation	[15]
Melanoma	DIS1RRCY	moderate	Genetic Variation	[15]
Arteriosclerosis	DISK5QGC	Limited	Biomarker	[16]

2 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 ADP-ribosylation factor-like protein 6-interacting protein 1 (ARL6IP1).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of ADP-ribosylation factor-like protein 6-interacting protein 1 (ARL6IP1).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of ADP-ribosylation factor-like protein 6-interacting protein 1 (ARL6IP1).	[18]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of ADP-ribosylation factor-like protein 6-interacting protein 1 (ARL6IP1).	[19]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of ADP-ribosylation factor-like protein 6-interacting protein 1 (ARL6IP1).	[20]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of ADP-ribosylation factor-like protein 6-interacting protein 1 (ARL6IP1).	[21]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of ADP-ribosylation factor-like protein 6-interacting protein 1 (ARL6IP1).	[22]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of ADP-ribosylation factor-like protein 6-interacting protein 1 (ARL6IP1).	[23]
Mifepristone	DMGZQEF	Approved	Mifepristone increases the expression of ADP-ribosylation factor-like protein 6-interacting protein 1 (ARL6IP1).	[24]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of ADP-ribosylation factor-like protein 6-interacting protein 1 (ARL6IP1).	[25]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of ADP-ribosylation factor-like protein 6-interacting protein 1 (ARL6IP1).	[27]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of ADP-ribosylation factor-like protein 6-interacting protein 1 (ARL6IP1).	[28]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the expression of ADP-ribosylation factor-like protein 6-interacting protein 1 (ARL6IP1).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of ADP-ribosylation factor-like protein 6-interacting protein 1 (ARL6IP1).	[29]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of ADP-ribosylation factor-like protein 6-interacting protein 1 (ARL6IP1).	[30]

References

• [1] Inhibition of ADP-ribosylation factor-like 6 interacting protein 1 suppresses proliferation and reduces tumor cell invasion in CaSki human cervical cancer cells.Mol Biol Rep. 2010 Dec;37(8):3819-25. doi: 10.1007/s11033-010-0037-y. Epub 2010 Mar 7.
• [2] 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.
• [3] Antiamyloidogenic Activity of A42-Binding Peptoid in Modulating Amyloid Oligomerization.Small. 2017 Jan;13(1). doi: 10.1002/smll.201602857. Epub 2016 Oct 7.
• [4] AIP1-mediated stress signaling in atherosclerosis and arteriosclerosis.Curr Atheroscler Rep. 2015 May;17(5):503. doi: 10.1007/s11883-015-0503-z.
• [5] ARL6IP1 mutation causes congenital insensitivity to pain, acromutilation and spastic paraplegia.Clin Genet. 2018 Jan;93(1):169-172. doi: 10.1111/cge.13048. Epub 2017 Aug 31.
• [6] Outcome and Genetic Factors in IgG4-Associated Autoimmune Pancreatitis and Cholangitis: A Single Center Experience.Gastroenterol Res Pract. 2017;2017:6126707. doi: 10.1155/2017/6126707. Epub 2017 Mar 2.
• [7] Suppression of inflammation and tissue damage by a hookworm recombinant protein in experimental colitis.Clin Transl Immunology. 2017 Oct 6;6(10):e157. doi: 10.1038/cti.2017.42. eCollection 2017 Oct.
• [8] Truncating ARL6IP1 variant as the genetic cause of fatal complicated hereditary spastic paraplegia.BMC Med Genet. 2019 Jul 4;20(1):119. doi: 10.1186/s12881-019-0851-6.
• [9] Low expression level of ASK1-interacting protein-1 correlated with tumor angiogenesis and poor survival in patients with esophageal squamous cell cancer.Onco Targets Ther. 2018 Nov 1;11:7699-7707. doi: 10.2147/OTT.S178131. eCollection 2018.
• [10] Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science. 2014 Jan 31;343(6170):506-511. doi: 10.1126/science.1247363.
• [11] A common genetic variant (97906C>A) of DAB2IP/AIP1 is associated with an increased risk and early onset of lung cancer in Chinese males.PLoS One. 2011;6(10):e26944. doi: 10.1371/journal.pone.0026944. Epub 2011 Oct 26.
• [12] Ca2+ binding to EF hands 1 and 3 is essential for the interaction of apoptosis-linked gene-2 with Alix/AIP1 in ocular melanoma.Biochemistry. 2004 Sep 7;43(35):11175-86. doi: 10.1021/bi048848d.
• [13] Global analysis of differentially expressed genes in androgen-independent prostate cancer.Prostate Cancer Prostatic Dis. 2007;10(2):167-74. doi: 10.1038/sj.pcan.4500933. Epub 2007 Jan 2.
• [14] Endothelial AIP1 Regulates Vascular Remodeling by Suppressing NADPH Oxidase-2.Front Physiol. 2018 Apr 20;9:396. doi: 10.3389/fphys.2018.00396. eCollection 2018.
• [15] AIP1 Expression in Tumor Niche Suppresses Tumor Progression and Metastasis.Cancer Res. 2015 Sep 1;75(17):3492-504. doi: 10.1158/0008-5472.CAN-15-0088. Epub 2015 Jul 2.
• [16] Short AIP1 (ASK1-Interacting Protein-1) Isoform Localizes to the Mitochondria and Promotes Vascular Dysfunction.Arterioscler Thromb Vasc Biol. 2020 Jan;40(1):112-127. doi: 10.1161/ATVBAHA.119.312976. Epub 2019 Oct 17.
• [17] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [18] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [19] Gene expression changes associated with cytotoxicity identified using cDNA arrays. Funct Integr Genomics. 2000 Sep;1(2):114-26.
• [20] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [21] 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.
• [22] [Construction of subtracted cDNA library in human Jurkat T cell line induced by arsenic trioxide in vitro]. Zhonghua Yu Fang Yi Xue Za Zhi. 2003 Nov;37(6):403-7.
• [23] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [24] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [25] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [26] 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.
• [27] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [28] 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.
• [29] 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.
• [30] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.