Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGSAM2E)

• DOT Name: Ras and EF-hand domain-containing protein (RASEF)
• Synonyms: Ras-related protein Rab-45
• Gene Name: RASEF
• Related Disease:
  Uveal Melanoma
  Breast neoplasm
  Lung cancer
  Lung carcinoma
  Melanoma
  Neoplasm
• UniProt ID: RASEF_HUMAN
• PDB ID: 2P5S; 2PMY
• Pfam ID: PF13499 ; PF00071
• Sequence:
  MEADGDGEELARLRSVFAACDANRSGRLEREEFRALCTELRVRPADAEAVFQRLDADRDG
  AITFQEFARGFLGSLRGGRRRDWGPLDPAPAVSEAGPETHDSEEDEGDEDAAAALATSCG
  PASPGRAWQDFQARLGDEAKFIPREEQVSTLYQNINLVEPRLIQPYEHVIKNFIREIRLQ
  STEMENLAIAVKRAQDKAAMQLSELEEEMDQRIQAAEHKTRKDEKRKAEEALSDLRRQYE
  TEVGDLQVTIKKLRKLEEQSKRVSQKEDVAALKKQIYDLSMENQKVKKDLLEAQTNIAFL
  QSELDALKSDYADQSLNTERDLEIIRAYTEDRNSLERQIEILQTANRKLHDSNDGLRSAL
  ENSYSKFNRSLHINNISPGNTISRSSPKFIGHSPQPLGYDRSSRSSYVDEDCDSLALCDP
  LQRTNCEVDSLPESCFDSGLSTLRDPNEYDSEVEYKHQRGFQRSHGVQESFGGDASDTDV
  PDIRDEETFGLEDVASVLDWKPQGSVSEGSIVSSSRKPISALSPQTDLVDDNAKSFSSQK
  AYKIVLAGDAAVGKSSFLMRLCKNEFRENISATLGVDFQMKTLIVDGERTVLQLWDTAGQ
  ERFRSIAKSYFRKADGVLLLYDVTCEKSFLNIREWVDMIEDAAHETVPIMLVGNKADIRD
  TAATEGQKCVPGHFGEKLAMTYGALFCETSAKDGSNIVEAVLHLAREVKKRTDKDDSRSI
  TNLTGTNSKKSPQMKNCCNG
• Function: Binds predominantly GDP, and also GTP. Acts as a dynein adapter protein that activates dynein-mediated transport and dynein-dynactin motility on microtubules.
• Tissue Specificity: Down-regulated in cutaneous melanoma cells but not in breast cancer cells.

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Uveal Melanoma	DISA7ZGL	Definitive	Biomarker	[1]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[2]
Lung cancer	DISCM4YA	Strong	Biomarker	[3]
Lung carcinoma	DISTR26C	Strong	Biomarker	[3]
Melanoma	DIS1RRCY	moderate	Altered Expression	[4]
Neoplasm	DISZKGEW	Limited	Biomarker	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Ras and EF-hand domain-containing protein (RASEF).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Ras and EF-hand domain-containing protein (RASEF).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Ras and EF-hand domain-containing protein (RASEF).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Ras and EF-hand domain-containing protein (RASEF).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Ras and EF-hand domain-containing protein (RASEF).	[9]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Ras and EF-hand domain-containing protein (RASEF).	[10]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Ras and EF-hand domain-containing protein (RASEF).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Ras and EF-hand domain-containing protein (RASEF).	[10]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Ras and EF-hand domain-containing protein (RASEF).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Ras and EF-hand domain-containing protein (RASEF).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Ras and EF-hand domain-containing protein (RASEF).	[11]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Ras and EF-hand domain-containing protein (RASEF).	[14]

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 Ras and EF-hand domain-containing protein (RASEF).	[12]

References

• [1] DNA Methylation and Uveal Melanoma.Chin Med J (Engl). 2018 Apr 5;131(7):845-851. doi: 10.4103/0366-6999.228229.
• [2] Mapping of a novel ocular and cutaneous malignant melanoma susceptibility locus to chromosome 9q21.32.J Natl Cancer Inst. 2005 Sep 21;97(18):1377-82. doi: 10.1093/jnci/dji280.
• [3] RASEF is a novel diagnostic biomarker and a therapeutic target for lung cancer.Mol Cancer Res. 2013 Aug;11(8):937-51. doi: 10.1158/1541-7786.MCR-12-0685-T. Epub 2013 May 16.
• [4] Near-genomewide RNAi screening for regulators of BRAF(V600E) -induced senescence identifies RASEF, a gene epigenetically silenced in melanoma.Pigment Cell Melanoma Res. 2014 Jul;27(4):640-52. doi: 10.1111/pcmr.12248. Epub 2014 May 14.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] Comparative effects of raloxifene, tamoxifen and estradiol on human osteoblasts in vitro: estrogen receptor dependent or independent pathways of raloxifene. J Steroid Biochem Mol Biol. 2009 Feb;113(3-5):281-9.
• [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] 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.
• [11] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [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] 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.
• [14] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.