Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTB84O0U)

• DOT Name: Transducin-like enhancer protein 6 (TLE6)
• Gene Name: TLE6
• Related Disease:
  Obsolete preimplantation embryonic lethality 1
  Acute myelogenous leukaemia
  Colonic neoplasm
  Digestive system neoplasm
• UniProt ID: TLE6_HUMAN
• Pfam ID: PF00400
• Sequence:
  MTSRDQPRPKGPPKSTSPCPGISNSESSPTLNYQGILNRLKQFPRFSPHFAAELESIYYS
  LHKIQQDVAEHHKQIGNVLQIVESCSQLQGFQSEEVSPAEPASPGTPQQVKDKTLQESSF
  EDIMATRSSDWLRRPLGEDNQPETQLFWDKEPWFWHDTLTEQLWRIFAGVHDEKAKPRDR
  QQAPGLGQESKAPGSCDPGTDPCPEDASTPRPPEASSSPPEGSQDRNTSWGVVQEPPGRA
  SRFLQSISWDPEDFEDAWKRPDALPGQSKRLAVPCKLEKMRILAHGELVLATAISSFTRH
  VFTCGRRGIKVWSLTGQVAEDRFPESHLPIQTPGAFLRTCLLSSNSRSLLTGGYNLASVS
  VWDLAAPSLHVKEQLPCAGLNCQALDANLDANLAFASFTSGVVRIWDLRDQSVVRDLKGY
  PDGVKSIVVKGYNIWTGGPDACLRCWDQRTIMKPLEYQFKSQIMSLSHSPQEDWVLLGMA
  NGQQWLQSTSGSQRHMVGQKDSVILSVKFSPFGQWWASVGMDDFLGVYSMPAGTKVFEVP
  EMSPVTCCDVSSNNRLVVTGSGEHASVYQITY
• Function: Regulates spermatogonia proliferation and cell cycle progression, potentially via regulation of cell cycle regulatory genes such as; CEBPB, CEBPA, CSF3, PCNA, and CDK4. Suppresses FOXG1/BF-1-mediated transcriptional repression by inhibiting interaction of the transcriptional corepressor TLE1 with FOXG1 which promotes cortical neuron differentiation. Acts as a transcriptional corepressor of NFATC1-mediated gene expression by contributing to PAX6-mediated repression; [Isoform 1]: As a member of the subcortical maternal complex (SCMC), plays an essential role for zygotes to progress beyond the first embryonic cell divisions via regulation of actin dynamics. Required for the formation of F-actin cytoplasmic lattices in oocytes which in turn are responsible for symmetric division of zygotes via the regulation of mitotic spindle formation and positioning.
• KEGG Pathway:
  Wnt sig.ling pathway (hsa04310)
  Notch sig.ling pathway (hsa04330)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Obsolete preimplantation embryonic lethality 1	DISZ97J0	Strong	Autosomal recessive	[1]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[2]
Colonic neoplasm	DISSZ04P	Limited	Altered Expression	[3]
Digestive system neoplasm	DISPOJCT	Limited	Biomarker	[3]

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 Transducin-like enhancer protein 6 (TLE6).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Transducin-like enhancer protein 6 (TLE6).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Transducin-like enhancer protein 6 (TLE6).	[5]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Transducin-like enhancer protein 6 (TLE6).	[6]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Transducin-like enhancer protein 6 (TLE6).	[7]
Pioglitazone	DMKJ485	Approved	Pioglitazone increases the expression of Transducin-like enhancer protein 6 (TLE6).	[8]

References

• [1] TLE6 mutation causes the earliest known human embryonic lethality. Genome Biol. 2015 Nov 5;16:240. doi: 10.1186/s13059-015-0792-0.
• [2] 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.
• [3] Novel roles for MLH3 deficiency and TLE6-like amplification in DNA mismatch repair-deficient gastrointestinal tumorigenesis and progression.PLoS Genet. 2008 Jun 13;4(6):e1000092. doi: 10.1371/journal.pgen.1000092.
• [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] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [7] Dose- and time-dependent effects of phenobarbital on gene expression profiling in human hepatoma HepaRG cells. Toxicol Appl Pharmacol. 2009 Feb 1;234(3):345-60.
• [8] Peroxisome proliferator activated receptor gamma (PPAR-gama) ligand pioglitazone regulated gene networks in term human primary trophoblast cells. Reprod Toxicol. 2018 Oct;81:99-107.
• [9] 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.