Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF9LV7L)

• DOT Name: Ankyrin repeat and SOCS box protein 2 (ASB2)
• Synonyms: ASB-2
• Gene Name: ASB2
• Related Disease:
  Acute myelogenous leukaemia
  Promyelocytic leukaemia
  Prostate cancer
  Prostate carcinoma
  T-cell acute lymphoblastic leukaemia
  Myotonic dystrophy
  Myotonic dystrophy type 1
• UniProt ID: ASB2_HUMAN
• Pfam ID: PF12796 ; PF13606 ; PF13637 ; PF07525
• Sequence:
  MATQISTRGSQCTIGQEEYSLYSSLSEDELVQMAIEQSLADKTRGPTTAEATASACTNRQ
  PAHFYPWTRSTAPPESSPARAPMGLFQGVMQKYSSSLFKTSQLAPADPLIKAIKDGDEEA
  LKTMIKEGKNLAEPNKEGWLPLHEAAYYGQVGCLKVLQRAYPGTIDQRTLQEETAVYLAT
  CRGHLDCLLSLLQAGAEPDISNKSRETPLYKACERKNAEAVKILVQHNADTNHRCNRGWT
  ALHESVSRNDLEVMQILVSGGAKVESKNAYGITPLFVAAQSGQLEALRFLAKYGADINTQ
  ASDNASALYEACKNEHEEVVEFLLSQGADANKTNKDGLLPLHIASKKGNYRIVQMLLPVT
  SRTRIRRSGVSPLHLAAERNHDEVLEALLSARFDVNTPLAPERARLYEDRRSSALYFAVV
  NNNVYATELLLQHGADPNRDVISPLLVAIRHGCLRTMQLLLDHGANIDAYIATHPTAFPA
  TIMFAMKCLSLLKFLMDLGCDGEPCFSCLYGNGPHPPAPQPSSRFNDAPAADKEPSVVQF
  CEFVSAPEVSRWAGPIIDVLLDYVGNVQLCSRLKEHIDSFEDWAVIKEKAEPPRPLAHLC
  RLRVRKAIGKYRIKLLDTLPLPGRLIRYLKYENTQ
• Function: Substrate-recognition component of a SCF-like ECS (Elongin-Cullin-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Mediates Notch-induced ubiquitination and degradation of substrates including TCF3/E2A and JAK2. Required during embryonic heart development for complete heart looping. Required for cardiomyocyte differentiation ; [Isoform 1]: Involved in myogenic differentiation and targets filamin FLNB for proteasomal degradation but not filamin FLNA. Also targets DES for proteasomal degradation. Acts as a negative regulator of skeletal muscle mass; [Isoform 2]: Targets filamins FLNA and FLNB for proteasomal degradation. This leads to enhanced adhesion of hematopoietic cells to fibronectin. Required for FLNA degradation in immature cardiomyocytes which is necessary for actin cytoskeleton remodeling, leading to proper organization of myofibrils and function of mature cardiomyocytes. Required for degradation of FLNA and FLNB in immature dendritic cells (DC) which enhances immature DC migration by promoting DC podosome formation and DC-mediated degradation of the extracellular matrix. Does not promote proteasomal degradation of tyrosine-protein kinases JAK1 or JAK2 in hematopoietic cells.
• Tissue Specificity: .Expressed in muscle cells.; [Isoform 2]: Expressed in hematopoietic cells.
• Reactome Pathway:
  Antigen processing (R-HSA-983168)
  Neddylation (R-HSA-8951664)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Genetic Variation	[1]
Promyelocytic leukaemia	DISYGG13	Strong	Biomarker	[2]
Prostate cancer	DISF190Y	Strong	Biomarker	[3]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[3]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Strong	Altered Expression	[4]
Myotonic dystrophy	DISNBEMX	Limited	Biomarker	[5]
Myotonic dystrophy type 1	DISJC0OX	Limited	Biomarker	[5]

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 Ankyrin repeat and SOCS box protein 2 (ASB2).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Ankyrin repeat and SOCS box protein 2 (ASB2).	[18]

14 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 Ankyrin repeat and SOCS box protein 2 (ASB2).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Ankyrin repeat and SOCS box protein 2 (ASB2).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Ankyrin repeat and SOCS box protein 2 (ASB2).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Ankyrin repeat and SOCS box protein 2 (ASB2).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Ankyrin repeat and SOCS box protein 2 (ASB2).	[11]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Ankyrin repeat and SOCS box protein 2 (ASB2).	[12]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Ankyrin repeat and SOCS box protein 2 (ASB2).	[13]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Ankyrin repeat and SOCS box protein 2 (ASB2).	[14]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Ankyrin repeat and SOCS box protein 2 (ASB2).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Ankyrin repeat and SOCS box protein 2 (ASB2).	[16]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Ankyrin repeat and SOCS box protein 2 (ASB2).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Ankyrin repeat and SOCS box protein 2 (ASB2).	[19]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Ankyrin repeat and SOCS box protein 2 (ASB2).	[20]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the expression of Ankyrin repeat and SOCS box protein 2 (ASB2).	[21]

References

• [1] 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.
• [2] ASB2 is an Elongin BC-interacting protein that can assemble with Cullin 5 and Rbx1 to reconstitute an E3 ubiquitin ligase complex.J Biol Chem. 2005 Feb 18;280(7):5468-74. doi: 10.1074/jbc.M413040200. Epub 2004 Dec 8.
• [3] Exploring targets of TET2-mediated methylation reprogramming as potential discriminators of prostate cancer progression.Clin Epigenetics. 2019 Mar 27;11(1):54. doi: 10.1186/s13148-019-0651-z.
• [4] The notch pathway promotes NF-B activation through Asb2 in T cell acute lymphoblastic leukemia cells.Cell Mol Biol Lett. 2018 Aug 9;23:37. doi: 10.1186/s11658-018-0102-4. eCollection 2018.
• [5] High-throughput analysis of the RNA-induced silencing complex in myotonic dystrophy type 1 patients identifies the dysregulation of miR-29c and its target ASB2.Cell Death Dis. 2018 Jun 28;9(7):729. doi: 10.1038/s41419-018-0769-5.
• [6] 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.
• [7] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [8] 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.
• [9] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] 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.
• [12] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [13] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [14] Progesterone promotes differentiation of human cord blood fetal T cells into T regulatory cells but suppresses their differentiation into Th17 cells. J Immunol. 2011 Aug 15;187(4):1778-87. doi: 10.4049/jimmunol.1003919. Epub 2011 Jul 18.
• [15] The effect of DNA methylation inhibitor 5-Aza-2'-deoxycytidine on human endometrial stromal cells. Hum Reprod. 2010 Nov;25(11):2859-69.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] Induction of class II major histocompatibility complex expression in human multiple myeloma cells by retinoid. Haematologica. 2007 Jan;92(1):115-20.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] Roles of acyl-CoA synthetase long-chain family member 5 and colony stimulating factor 2 in inhibition of palmitic or stearic acids in lung cancer cell proliferation and metabolism. Cell Biol Toxicol. 2021 Feb;37(1):15-34. doi: 10.1007/s10565-020-09520-w. Epub 2020 Apr 28.