Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOR82ID)

• DOT Name: Cytohesin-4 (CYTH4)
• Synonyms: PH, SEC7 and coiled-coil domain-containing protein 4
• Gene Name: CYTH4
• Related Disease:
  Alzheimer disease
  Bipolar disorder
  Schizophrenia
• UniProt ID: CYH4_HUMAN
• Pfam ID: PF00169 ; PF01369
• Sequence:
  MDLCHPEPAELSSGETEELQRIKWHRKQLLEDIQKLKDEIADVFAQIDCFESAEESRMAQ
  KEKELCIGRKKFNMDPAKGIQYFIEHKLLTPDVQDIARFLYKGEGLNKTAIGTYLGERDP
  INLQVLQAFVDCHEFANLNLVQALRQFLWSFRLPGEAQKIDRMMEAFATRYCLCNPGVFQ
  STDTCYVLSFSIIMLNTSLHNPNVRDRPPFERFVSMNRGINNGSDLPEDQLRNLFDSIKS
  EPFSIPEDDGNDLTHTFFNPDREGWLLKLGGRVKTWKRRWFILTDNCLYYFEFTTDKEPR
  GIIPLENLSVQKVDDPKKPFCLELYNPSCRGQKIKACKTDGDGRVVEGKHESYRISATSA
  EERDQWIESIRASITRVPFYDLVSTRKKKIASKQ
• Function: Promotes guanine-nucleotide exchange on ARF1 and ARF5. Promotes the activation of ARF factors through replacement of GDP with GTP.
• Tissue Specificity: Expressed predominantly in peripheral blood leukocytes.
• KEGG Pathway:
  Phospholipase D sig.ling pathway (hsa04072)
  Endocytosis (hsa04144)
  Pathogenic Escherichia coli infection (hsa05130)
  Shigellosis (hsa05131)
  Salmonella infection (hsa05132)
• Reactome Pathway: Intra-Golgi traffic (R-HSA-6811438)

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	Genetic Variation	[1]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[2]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[3]

9 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 Cytohesin-4 (CYTH4).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Cytohesin-4 (CYTH4).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Cytohesin-4 (CYTH4).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Cytohesin-4 (CYTH4).	[7]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Cytohesin-4 (CYTH4).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Cytohesin-4 (CYTH4).	[9]
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of Cytohesin-4 (CYTH4).	[10]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of Cytohesin-4 (CYTH4).	[11]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Cytohesin-4 (CYTH4).	[13]

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 increases the methylation of Cytohesin-4 (CYTH4).	[12]

References

• [1] Dominant and Protective Role of the CYTH4 Primate-Specific GTTT-Repeat Longer Alleles Against Neurodegeneration.J Mol Neurosci. 2015 Jul;56(3):593-6. doi: 10.1007/s12031-015-0542-5. Epub 2015 Apr 1.
• [2] A primate-specific functional GTTT-repeat in the core promoter of CYTH4 is linked to bipolar disorder in human.Prog Neuropsychopharmacol Biol Psychiatry. 2015 Jan 2;56:161-7. doi: 10.1016/j.pnpbp.2014.09.001. Epub 2014 Sep 18.
• [3] Support for "Disease-Only" Genotypes and Excess of Homozygosity at the CYTH4 Primate-Specific GTTT-Repeat in Schizophrenia.Genet Test Mol Biomarkers. 2017 Aug;21(8):485-490. doi: 10.1089/gtmb.2016.0422. Epub 2017 Jul 19.
• [4] 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.
• [5] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [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] 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.
• [8] Inorganic arsenic exposure promotes malignant progression by HDAC6-mediated down-regulation of HTRA1. J Appl Toxicol. 2023 Aug;43(8):1214-1224. doi: 10.1002/jat.4457. Epub 2023 Mar 11.
• [9] 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.
• [10] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [11] Gene-expression profiling during curcumin-induced apoptosis reveals downregulation of CXCR4. Exp Hematol. 2007 Jan;35(1):84-95.
• [12] 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.
• [13] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.