Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0WXRWT)

• DOT Name: DNA-binding death effector domain-containing protein 2 (DEDD2)
• Synonyms: DED-containing protein FLAME-3; FADD-like anti-apoptotic molecule 3
• Gene Name: DEDD2
• UniProt ID: DEDD2_HUMAN
• Pfam ID: PF01335 ; PF20694
• Sequence:
  MALSGSTPAPCWEEDECLDYYGMLSLHRMFEVVGGQLTECELELLAFLLDEAPGAAGGLA
  RARSGLELLLELERRGQCDESNLRLLGQLLRVLARHDLLPHLARKRRRPVSPERYSYGTS
  SSSKRTEGSCRRRRQSSSSANSQQGQWETGSPPTKRQRRSRGRPSGGARRRRRGAPAAPQ
  QQSEPARPSSEGKVTCDIRLRVRAEYCEHGPALEQGVASRRPQALARQLDVFGQATAVLR
  SRDLGSVVCDIKFSELSYLDAFWGDYLSGALLQALRGVFLTEALREAVGREAVRLLVSVD
  EADYEAGRRRLLLMEEEGGRRPTEAS
• Function: May play a critical role in death receptor-induced apoptosis and may target CASP8 and CASP10 to the nucleus. May regulate degradation of intermediate filaments during apoptosis. May play a role in the general transcription machinery in the nucleus and might be an important regulator of the activity of GTF3C3.
• Tissue Specificity: Expressed in most tissues. High levels were found in liver, kidney, heart, ovary, spleen, testes, skeletal muscle and peripheral blood leukocytes. Expression was absent or low in colon and small intestine. Expression is relatively high in the tumor cell lines chronic myologenous leukemia K-562 and the colorectal adenocarcinoma SW480. Expression is moderate in the cervical carcinoma HeLa, the Burkitt's lymphoma Raji, the lung carcinoma A-549, and the melanoma G-361. In contrast, two leukemia cell lines, HL-60 (promyelocytic leukemia) and MOLT-4 (lymphoblastic leukemia), show relatively low levels.

Molecular Interaction Atlas (MIA) of This DOT

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 DNA-binding death effector domain-containing protein 2 (DEDD2).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of DNA-binding death effector domain-containing protein 2 (DEDD2).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of DNA-binding death effector domain-containing protein 2 (DEDD2).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of DNA-binding death effector domain-containing protein 2 (DEDD2).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of DNA-binding death effector domain-containing protein 2 (DEDD2).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of DNA-binding death effector domain-containing protein 2 (DEDD2).	[5]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of DNA-binding death effector domain-containing protein 2 (DEDD2).	[6]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of DNA-binding death effector domain-containing protein 2 (DEDD2).	[7]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial increases the expression of DNA-binding death effector domain-containing protein 2 (DEDD2).	[8]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium increases the expression of DNA-binding death effector domain-containing protein 2 (DEDD2).	[8]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of DNA-binding death effector domain-containing protein 2 (DEDD2).	[9]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of DNA-binding death effector domain-containing protein 2 (DEDD2).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of DNA-binding death effector domain-containing protein 2 (DEDD2).	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of DNA-binding death effector domain-containing protein 2 (DEDD2).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of DNA-binding death effector domain-containing protein 2 (DEDD2).	[14]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of DNA-binding death effector domain-containing protein 2 (DEDD2).	[15]
crotylaldehyde	DMTWRQI	Investigative	crotylaldehyde increases the expression of DNA-binding death effector domain-containing protein 2 (DEDD2).	[16]

References

• [1] 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.
• [2] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [3] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] 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.
• [6] LncRNA UCA1 attenuates autophagy-dependent cell death through blocking autophagic flux under arsenic stress. Toxicol Lett. 2018 Mar 1;284:195-204. doi: 10.1016/j.toxlet.2017.12.009. Epub 2017 Dec 15.
• [7] Bortezomib induces caspase-dependent apoptosis in Hodgkin lymphoma cell lines and is associated with reduced c-FLIP expression: a gene expression profiling study with implications for potential combination therapies. Leuk Res. 2008 Feb;32(2):275-85. doi: 10.1016/j.leukres.2007.05.024. Epub 2007 Jul 19.
• [8] Motexafin gadolinium and zinc induce oxidative stress responses and apoptosis in B-cell lymphoma lines. Cancer Res. 2005 Dec 15;65(24):11676-88.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] 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.
• [11] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [12] 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.
• [13] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [14] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [15] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [16] Gene expression profile and cytotoxicity of human bronchial epithelial cells exposed to crotonaldehyde. Toxicol Lett. 2010 Aug 16;197(2):113-22.