Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8PQPZ1)

• DOT Name: Polyamine-modulated factor 1 (PMF1)
• Synonyms: PMF-1
• Gene Name: PMF1
• Related Disease:
  Bladder cancer
  Intracerebral hemorrhage
  Neoplasm
  Urinary bladder cancer
  Urinary bladder neoplasm
  Stroke
• UniProt ID: PMF1_HUMAN
• PDB ID: 5LSJ; 5LSK
• Pfam ID: PF03980
• Sequence:
  MAEASSANLGSGCEEKRHEGSSSESVPPGTTISRVKLLDTMVDTFLQKLVAAGSYQRFTD
  CYKCFYQLQPAMTQQIYDKFIAQLQTSIREEISDIKEEGNLEAVLNALDKIVEEGKVRKE
  PAWRPSGIPEKDLHSVMAPYFLQQRDTLRRHVQKQEAENQQLADAVLAGRRQVEELQLQV
  QAQQQAWQALHREQRELVAVLREPE
• Function: Part of the MIS12 complex which is required for normal chromosome alignment and segregation and kinetochore formation during mitosis. May act as a cotranscription partner of NFE2L2 involved in regulation of polyamine-induced transcription of SSAT.
• Tissue Specificity: Highest levels of expression in heart and skeletal muscle, with significant levels expressed in kidney and liver.
• Reactome Pathway:
  Separation of Sister Chromatids (R-HSA-2467813)
  Resolution of Sister Chromatid Cohesion (R-HSA-2500257)
  RHO GTPases Activate Formins (R-HSA-5663220)
  Mitotic Prometaphase (R-HSA-68877)
  EML4 and NUDC in mitotic spindle formation (R-HSA-9648025)
  Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal (R-HSA-141444)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bladder cancer	DISUHNM0	Strong	Posttranslational Modification	[1]
Intracerebral hemorrhage	DISC81BT	Strong	Genetic Variation	[2]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[1]
Urinary bladder cancer	DISDV4T7	Strong	Posttranslational Modification	[1]
Urinary bladder neoplasm	DIS7HACE	Strong	Posttranslational Modification	[1]
Stroke	DISX6UHX	moderate	Genetic Variation	[3]

4 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 Polyamine-modulated factor 1 (PMF1).	[4]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Polyamine-modulated factor 1 (PMF1).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Polyamine-modulated factor 1 (PMF1).	[11]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Polyamine-modulated factor 1 (PMF1).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Polyamine-modulated factor 1 (PMF1).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Polyamine-modulated factor 1 (PMF1).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Polyamine-modulated factor 1 (PMF1).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Polyamine-modulated factor 1 (PMF1).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Polyamine-modulated factor 1 (PMF1).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Polyamine-modulated factor 1 (PMF1).	[13]

References

• [1] Polyamine-modulated factor-1 methylation predicts Bacillus Calmette-Gurin response in patients with high-grade non-muscle-invasive bladder carcinoma.Eur Urol. 2013 Feb;63(2):364-70. doi: 10.1016/j.eururo.2012.05.050. Epub 2012 Jun 5.
• [2] Meta-analysis of genome-wide association studies identifies 1q22 as a susceptibility locus for intracerebral hemorrhage.Am J Hum Genet. 2014 Apr 3;94(4):511-21. doi: 10.1016/j.ajhg.2014.02.012. Epub 2014 Mar 20.
• [3] Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.Nat Genet. 2018 Apr;50(4):524-537. doi: 10.1038/s41588-018-0058-3. Epub 2018 Mar 12.
• [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] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [9] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] 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.
• [12] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [13] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.