Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6SM2GD)

• DOT Name: Protein PML (PML)
• Synonyms: E3 SUMO-protein ligase PML; EC 2.3.2.-; Promyelocytic leukemia protein; RING finger protein 71; RING-type E3 SUMO transferase PML; Tripartite motif-containing protein 19; TRIM19
• Gene Name: PML
• UniProt ID: PML_HUMAN
• PDB ID: 1BOR; 2MVW; 2MWX; 4WJN; 4WJO; 5YUF; 6IMQ; 6UYO; 6UYP; 6UYQ; 6UYR; 6UYS; 6UYT; 6UYU; 6UYV; 8DJH; 8DJI; 8J25; 8J2P
• EC Number: 2.3.2.-
• Pfam ID: PF12126 ; PF00643 ; PF00097
• Sequence:
  MEPAPARSPRPQQDPARPQEPTMPPPETPSEGRQPSPSPSPTERAPASEEEFQFLRCQQC
  QAEAKCPKLLPCLHTLCSGCLEASGMQCPICQAPWPLGADTPALDNVFFESLQRRLSVYR
  QIVDAQAVCTRCKESADFWCFECEQLLCAKCFEAHQWFLKHEARPLAELRNQSVREFLDG
  TRKTNNIFCSNPNHRTPTLTSIYCRGCSKPLCCSCALLDSSHSELKCDISAEIQQRQEEL
  DAMTQALQEQDSAFGAVHAQMHAAVGQLGRARAETEELIRERVRQVVAHVRAQERELLEA
  VDARYQRDYEEMASRLGRLDAVLQRIRTGSALVQRMKCYASDQEVLDMHGFLRQALCRLR
  QEEPQSLQAAVRTDGFDEFKVRLQDLSSCITQGKDAAVSKKASPEAASTPRDPIDVDLPE
  EAERVKAQVQALGLAEAQPMAVVQSVPGAHPVPVYAFSIKGPSYGEDVSNTTTAQKRKCS
  QTQCPRKVIKMESEEGKEARLARSSPEQPRPSTSKAVSPPHLDGPPSPRSPVIGSEVFLP
  NSNHVASGAGEAEERVVVISSSEDSDAENSSSRELDDSSSESSDLQLEGPSTLRVLDENL
  ADPQAEDRPLVFFDLKIDNETQKISQLAAVNRESKFRVVIQPEAFFSIYSKAVSLEVGLQ
  HFLSFLSSMRRPILACYKLWGPGLPNFFRALEDINRLWEFQEAISGFLAALPLIRERVPG
  ASSFKLKNLAQTYLARNMSERSAMAAVLAMRDLCRLLEVSPGPQLAQHVYPFSSLQCFAS
  LQPLVQAAVLPRAEARLLALHNVSFMELLSAHRRDRQGGLKKYSRYLSLQTTTLPPAQPA
  FNLQALGTYFEGLLEGPALARAEGVSTPLAGRGLAERASQQS
• Function: Functions via its association with PML-nuclear bodies (PML-NBs) in a wide range of important cellular processes, including tumor suppression, transcriptional regulation, apoptosis, senescence, DNA damage response, and viral defense mechanisms. Acts as the scaffold of PML-NBs allowing other proteins to shuttle in and out, a process which is regulated by SUMO-mediated modifications and interactions. Inhibits EIF4E-mediated mRNA nuclear export by reducing EIF4E affinity for the 5' 7-methylguanosine (m7G) cap of target mRNAs. Isoform PML-4 has a multifaceted role in the regulation of apoptosis and growth suppression: activates RB1 and inhibits AKT1 via interactions with PP1 and PP2A phosphatases respectively, negatively affects the PI3K pathway by inhibiting MTOR and activating PTEN, and positively regulates p53/TP53 by acting at different levels (by promoting its acetylation and phosphorylation and by inhibiting its MDM2-dependent degradation). Isoform PML-4 also: acts as a transcriptional repressor of TBX2 during cellular senescence and the repression is dependent on a functional RBL2/E2F4 repressor complex, regulates double-strand break repair in gamma-irradiation-induced DNA damage responses via its interaction with WRN, acts as a negative regulator of telomerase by interacting with TERT, and regulates PER2 nuclear localization and circadian function. Isoform PML-6 inhibits specifically the activity of the tetrameric form of PKM. The nuclear isoforms (isoform PML-1, isoform PML-2, isoform PML-3, isoform PML-4 and isoform PML-5) in concert with SATB1 are involved in local chromatin-loop remodeling and gene expression regulation at the MHC-I locus. Isoform PML-2 is required for efficient IFN-gamma induced MHC II gene transcription via regulation of CIITA. Cytoplasmic PML is involved in the regulation of the TGF-beta signaling pathway. PML also regulates transcription activity of ELF4 and can act as an important mediator for TNF-alpha- and IFN-alpha-mediated inhibition of endothelial cell network formation and migration; Exhibits antiviral activity against both DNA and RNA viruses. The antiviral activity can involve one or several isoform(s) and can be enhanced by the permanent PML-NB-associated protein DAXX or by the recruitment of p53/TP53 within these structures. Isoform PML-4 restricts varicella zoster virus (VZV) via sequestration of virion capsids in PML-NBs thereby preventing their nuclear egress and inhibiting formation of infectious virus particles. The sumoylated isoform PML-4 restricts rabies virus by inhibiting viral mRNA and protein synthesis. The cytoplasmic isoform PML-14 can restrict herpes simplex virus-1 (HHV-1) replication by sequestering the viral E3 ubiquitin-protein ligase ICP0 in the cytoplasm. Isoform PML-6 shows restriction activity towards human cytomegalovirus (HHV-5) and influenza A virus strains PR8(H1N1) and ST364(H3N2). Sumoylated isoform PML-4 and isoform PML-12 show antiviral activity against encephalomyocarditis virus (EMCV) by promoting nuclear sequestration of viral polymerase (P3D-POL) within PML NBs. Isoform PML-3 exhibits antiviral activity against poliovirus by inducing apoptosis in infected cells through the recruitment and the activation of p53/TP53 in the PML-NBs. Isoform PML-3 represses human foamy virus (HFV) transcription by complexing the HFV transactivator, bel1/tas, preventing its binding to viral DNA. PML may positively regulate infectious hepatitis C viral (HCV) production and isoform PML-2 may enhance adenovirus transcription. Functions as an E3 SUMO-protein ligase that sumoylates (HHV-5) immediate early protein IE1, thereby participating in the antiviral response. Isoforms PML-3 and PML-6 display the highest levels of sumoylation activity.
• KEGG Pathway:
  Ubiquitin mediated proteolysis (hsa04120)
  Endocytosis (hsa04144)
  Influenza A (hsa05164)
  Herpes simplex virus 1 infection (hsa05168)
  Pathways in cancer (hsa05200)
  Transcriptio.l misregulation in cancer (hsa05202)
  Acute myeloid leukemia (hsa05221)
• Reactome Pathway:
  (Name not found)
  SUMOylation of ubiquitinylation proteins (R-HSA-3232142)
  Regulation of TP53 Activity through Acetylation (R-HSA-6804758)
  Interferon gamma signaling (R-HSA-877300)
  Regulation of RUNX1 Expression and Activity (R-HSA-8934593)
  Regulation of PTEN localization (R-HSA-8948747)
  HCMV Early Events (R-HSA-9609690)
  SUMOylation of DNA damage response and repair proteins (R-HSA-3108214)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Protein PML (PML) decreases the response to substance of Arsenic trioxide.	[24]
Rapamycin Immunosuppressant Drug	DM678IB	Investigative	Protein PML (PML) decreases the response to substance of Rapamycin Immunosuppressant Drug.	[25]
PP-242	DM2348V	Investigative	Protein PML (PML) decreases the response to substance of PP-242.	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Protein PML (PML).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein PML (PML).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein PML (PML).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Protein PML (PML).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein PML (PML).	[5]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Protein PML (PML).	[7]
Selenium	DM25CGV	Approved	Selenium increases the expression of Protein PML (PML).	[8]
Malathion	DMXZ84M	Approved	Malathion decreases the expression of Protein PML (PML).	[9]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Protein PML (PML).	[10]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Protein PML (PML).	[11]
Mitoxantrone	DMM39BF	Approved	Mitoxantrone affects the mutagenesis of Protein PML (PML).	[12]
Sulindac	DM2QHZU	Approved	Sulindac increases the expression of Protein PML (PML).	[13]
Ibuprofen	DM8VCBE	Approved	Ibuprofen affects the expression of Protein PML (PML).	[14]
Rofecoxib	DM3P5DA	Approved	Rofecoxib increases the expression of Protein PML (PML).	[14]
Epirubicin	DMPDW6T	Approved	Epirubicin affects the mutagenesis of Protein PML (PML).	[12]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Protein PML (PML).	[15]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Protein PML (PML).	[8]
Puerarin	DMJIMXH	Phase 2	Puerarin decreases the expression of Protein PML (PML).	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Protein PML (PML).	[18]
ELLAGIC ACID	DMX8BS5	Investigative	ELLAGIC ACID decreases the expression of Protein PML (PML).	[23]

3 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the degradation of Protein PML (PML).	[6]
MG-132	DMKA2YS	Preclinical	MG-132 decreases the degradation of Protein PML (PML).	[21]
Cycloheximide	DMGDA3C	Investigative	Cycloheximide decreases the degradation of Protein PML (PML).	[21]

5 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 increases the methylation of Protein PML (PML).	[17]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Protein PML (PML).	[19]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Protein PML (PML).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Protein PML (PML).	[22]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Protein PML (PML).	[20]

References

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• [2] Effect of retinoic acid on gene expression in human conjunctival epithelium: secretory phospholipase A2 mediates retinoic acid induction of MUC16. Invest Ophthalmol Vis Sci. 2005 Nov;46(11):4050-61.
• [3] 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.
• [4] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [5] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [6] RNF4 is a poly-SUMO-specific E3 ubiquitin ligase required for arsenic-induced PML degradation. Nat Cell Biol. 2008 May;10(5):538-46. doi: 10.1038/ncb1716. Epub 2008 Apr 13.
• [7] Chemosensitivity enhancement toward arsenic trioxide by inhibition of histone deacetylase in NB4 cell line. J Int Med Res. 2016 Aug;44(4):882-92. doi: 10.1177/0300060516646238. Epub 2016 May 17.
• [8] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [9] Malathion induced cancer-linked gene expression in human lymphocytes. Environ Res. 2020 Mar;182:109131. doi: 10.1016/j.envres.2020.109131. Epub 2020 Jan 10.
• [10] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [11] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [12] Evidence for direct involvement of epirubicin in the formation of chromosomal translocations in t(15;17) therapy-related acute promyelocytic leukemia. Blood. 2010 Jan 14;115(2):326-30. doi: 10.1182/blood-2009-07-235051. Epub 2009 Nov 2.
• [13] Differential gene expression of sulindac-treated human breast epithelial cells. Int J Oncol. 2005 Dec;27(6):1727-36.
• [14] Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain. Pain. 2007 Mar;128(1-2):136-47.
• [15] Anti-proliferative and gene expression actions of resveratrol in breast cancer cells in vitro. Oncotarget. 2014 Dec 30;5(24):12891-907.
• [16] [Apoptosis of NB4 cells induced by flavonoids of puerarin in vitro]. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2010 Apr;18(2):326-9.
• [17] 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.
• [18] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [19] 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.
• [20] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [21] Solubility shift and SUMOylaltion of promyelocytic leukemia (PML) protein in response to arsenic(III) and fate of the SUMOylated PML. Toxicol Appl Pharmacol. 2015 Sep 15;287(3):191-201. doi: 10.1016/j.taap.2015.05.018. Epub 2015 Jun 3.
• [22] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [23] Interactive gene expression pattern in prostate cancer cells exposed to phenolic antioxidants. Life Sci. 2002 Mar 1;70(15):1821-39.
• [24] Mutations affecting both the rearranged and the unrearranged PML alleles in refractory acute promyelocytic leukaemia. Br J Haematol. 2016 Mar;172(6):909-13. doi: 10.1111/bjh.13910. Epub 2016 Jan 5.
• [25] PML mediates glioblastoma resistance to mammalian target of rapamycin (mTOR)-targeted therapies. Proc Natl Acad Sci U S A. 2013 Mar 12;110(11):4339-44. doi: 10.1073/pnas.1217602110. Epub 2013 Feb 25.