Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTMWP8L)

• DOT Name: Pumilio homolog 1 (PUM1)
• Synonyms: HsPUM; Pumilio-1
• Gene Name: PUM1
• Related Disease:
  Invasive breast carcinoma
  Spinocerebellar ataxia type 1
  Breast neoplasm
  Cerebellar ataxia
  Cryptorchidism
  Epithelial ovarian cancer
  Inflammatory breast cancer
  Intellectual disability
  Intrahepatic cholestasis of pregnancy
  Neoplasm
  Non-small-cell lung cancer
  Obesity
  Osteoporosis
  Ovarian cancer
  Ovarian neoplasm
  Spinocerebellar ataxia 47
• UniProt ID: PUM1_HUMAN
• PDB ID: 1IB2; 1M8W; 1M8X; 1M8Y; 1M8Z; 2YJY; 3BSB; 3BSX; 3Q0L; 3Q0M; 3Q0N; 3Q0O; 3Q0P; 5YKH; 5YKI
• Pfam ID: PF00806
• Sequence:
  MSVACVLKRKAVLWQDSFSPHLKHHPQEPANPNMPVVLTSGTGSQAQPQPAANQALAAGT
  HSSPVPGSIGVAGRSQDDAMVDYFFQRQHGEQLGGGGSGGGGYNNSKHRWPTGDNIHAEH
  QVRSMDELNHDFQALALEGRAMGEQLLPGKKFWETDESSKDGPKGIFLGDQWRDSAWGTS
  DHSVSQPIMVQRRPGQSFHVNSEVNSVLSPRSESGGLGVSMVEYVLSSSPGDSCLRKGGF
  GPRDADSDENDKGEKKNKGTFDGDKLGDLKEEGDVMDKTNGLPVQNGIDADVKDFSRTPG
  NCQNSANEVDLLGPNQNGSEGLAQLTSTNGAKPVEDFSNMESQSVPLDPMEHVGMEPLQF
  DYSGTQVPVDSAAATVGLFDYNSQQQLFQRPNALAVQQLTAAQQQQYALAAAHQPHIGLA
  PAAFVPNPYIISAAPPGTDPYTAGLAAAATLGPAVVPHQYYGVTPWGVYPASLFQQQAAA
  AAAATNSANQQTTPQAQQGQQQVLRGGASQRPLTPNQNQQGQQTDPLVAAAAVNSALAFG
  QGLAAGMPGYPVLAPAAYYDQTGALVVNAGARNGLGAPVRLVAPAPVIISSSAAQAAVAA
  AAASANGAAGGLAGTTNGPFRPLGTQQPQPQPQQQPNNNLASSSFYGNNSLNSNSQSSSL
  FSQGSAQPANTSLGFGSSSSLGATLGSALGGFGTAVANSNTGSGSRRDSLTGSSDLYKRT
  SSSLTPIGHSFYNGLSFSSSPGPVGMPLPSQGPGHSQTPPPSLSSHGSSSSLNLGGLTNG
  SGRYISAAPGAEAKYRSASSASSLFSPSSTLFSSSRLRYGMSDVMPSGRSRLLEDFRNNR
  YPNLQLREIAGHIMEFSQDQHGSRFIQLKLERATPAERQLVFNEILQAAYQLMVDVFGNY
  VIQKFFEFGSLEQKLALAERIRGHVLSLALQMYGCRVIQKALEFIPSDQQNEMVRELDGH
  VLKCVKDQNGNHVVQKCIECVQPQSLQFIIDAFKGQVFALSTHPYGCRVIQRILEHCLPD
  QTLPILEELHQHTEQLVQDQYGNYVIQHVLEHGRPEDKSKIVAEIRGNVLVLSQHKFASN
  VVEKCVTHASRTERAVLIDEVCTMNDGPHSALYTMMKDQYANYVVQKMIDVAEPGQRKIV
  MHKIRPHIATLRKYTYGKHILAKLEKYYMKNGVDLGPICGPPNGII
• Function: Sequence-specific RNA-binding protein that acts as a post-transcriptional repressor by binding the 3'-UTR of mRNA targets. Binds to an RNA consensus sequence, the Pumilio Response Element (PRE), 5'-UGUANAUA-3', that is related to the Nanos Response Element (NRE). Mediates post-transcriptional repression of transcripts via different mechanisms: acts via direct recruitment of the CCR4-POP2-NOT deadenylase leading to translational inhibition and mRNA degradation. Also mediates deadenylation-independent repression by promoting accessibility of miRNAs. Following growth factor stimulation, phosphorylated and binds to the 3'-UTR of CDKN1B/p27 mRNA, inducing a local conformational change that exposes miRNA-binding sites, promoting association of miR-221 and miR-222, efficient suppression of CDKN1B/p27 expression, and rapid entry to the cell cycle. Acts as a post-transcriptional repressor of E2F3 mRNAs by binding to its 3'-UTR and facilitating miRNA regulation. Represses a program of genes necessary to maintain genomic stability such as key mitotic, DNA repair and DNA replication factors. Its ability to repress those target mRNAs is regulated by the lncRNA NORAD (non-coding RNA activated by DNA damage) which, due to its high abundance and multitude of PUMILIO binding sites, is able to sequester a significant fraction of PUM1 and PUM2 in the cytoplasm. Involved in neuronal functions by regulating ATXN1 mRNA levels: acts by binding to the 3'-UTR of ATXN1 transcripts, leading to their down-regulation independently of the miRNA machinery. Plays a role in cytoplasmic sensing of viral infection. In testis, acts as a post-transcriptional regulator of spermatogenesis by binding to the 3'-UTR of mRNAs coding for regulators of p53/TP53. Involved in embryonic stem cell renewal by facilitating the exit from the ground state: acts by targeting mRNAs coding for naive pluripotency transcription factors and accelerates their down-regulation at the onset of differentiation. Binds specifically to miRNA MIR199A precursor, with PUM2, regulates miRNA MIR199A expression at a postranscriptional level.
• Tissue Specificity: Expressed in brain, heart, kidney, muscle, intestine and stomach. Not expressed in cerebellum, corpus callosum, caudate nucleus, hippocampus, medulla oblongata and putamen. Expressed in all fetal tissues tested.
• KEGG Pathway: Spinocerebellar ataxia (hsa05017)
• Reactome Pathway: Golgi Associated Vesicle Biogenesis (R-HSA-432722)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Invasive breast carcinoma	DISANYTW	Definitive	Biomarker	[1]
Spinocerebellar ataxia type 1	DISF7BO2	Definitive	Biomarker	[2]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[3]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[4]
Cryptorchidism	DISYUD2P	Strong	Biomarker	[5]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[6]
Inflammatory breast cancer	DIS3QRWA	Strong	Biomarker	[7]
Intellectual disability	DISMBNXP	Strong	Biomarker	[5]
Intrahepatic cholestasis of pregnancy	DISMHS5F	Strong	Altered Expression	[8]
Neoplasm	DISZKGEW	Strong	Biomarker	[9]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[10]
Obesity	DIS47Y1K	Strong	Genetic Variation	[11]
Osteoporosis	DISF2JE0	Strong	Genetic Variation	[11]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[6]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[6]
Spinocerebellar ataxia 47	DISXC1FU	Moderate	Autosomal dominant	[5]

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 Pumilio homolog 1 (PUM1).	[12]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Pumilio homolog 1 (PUM1).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Pumilio homolog 1 (PUM1).	[19]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Pumilio homolog 1 (PUM1).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Pumilio homolog 1 (PUM1).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Pumilio homolog 1 (PUM1).	[14]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Pumilio homolog 1 (PUM1).	[15]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of Pumilio homolog 1 (PUM1).	[17]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Pumilio homolog 1 (PUM1).	[18]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of Pumilio homolog 1 (PUM1).	[14]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Pumilio homolog 1 (PUM1).	[20]

References

• [1] Selecting housekeeping genes as references for the normalization of quantitative PCR data in breast cancer.Clin Transl Oncol. 2014 Feb;16(2):184-90. doi: 10.1007/s12094-013-1058-5. Epub 2013 May 30.
• [2] Pumilio1 haploinsufficiency leads to SCA1-like neurodegeneration by increasing wild-type Ataxin1 levels.Cell. 2015 Mar 12;160(6):1087-98. doi: 10.1016/j.cell.2015.02.012.
• [3] Statistical modeling for selecting housekeeper genes.Genome Biol. 2004;5(8):R59. doi: 10.1186/gb-2004-5-8-r59. Epub 2004 Jul 29.
• [4] Investigating PUM1 mutations in a Taiwanese cohort with cerebellar ataxia.Parkinsonism Relat Disord. 2019 Sep;66:220-223. doi: 10.1016/j.parkreldis.2019.08.004. Epub 2019 Aug 7.
• [5] PUM1 haploinsufficiency is associated with syndromic neurodevelopmental delay and epilepsy. Am J Med Genet A. 2020 Mar;182(3):591-594. doi: 10.1002/ajmg.a.61463. Epub 2019 Dec 20.
• [6] circPUM1 Promotes Tumorigenesis and Progression of Ovarian Cancer by Sponging miR-615-5p and miR-6753-5p.Mol Ther Nucleic Acids. 2019 Dec 6;18:882-892. doi: 10.1016/j.omtn.2019.09.032. Epub 2019 Oct 23.
• [7] Identification of genes for normalization of real-time RT-PCR data in breast carcinomas.BMC Cancer. 2008 Jan 22;8:20. doi: 10.1186/1471-2407-8-20.
• [8] Identification of genes for normalization of real-time RT-PCR data in placental tissues from intrahepatic cholestasis of pregnancy.Placenta. 2016 Dec;48:133-135. doi: 10.1016/j.placenta.2016.10.017. Epub 2016 Nov 2.
• [9] SPIN1 is a proto-oncogene and SPIN3 is a tumor suppressor in human seminoma.Oncotarget. 2018 Aug 21;9(65):32466-32477. doi: 10.18632/oncotarget.25977. eCollection 2018 Aug 21.
• [10] PUM1 knockdown prevents tumor progression by activating the PERK/eIF2/ATF4 signaling pathway in pancreatic adenocarcinoma cells.Cell Death Dis. 2019 Aug 8;10(8):595. doi: 10.1038/s41419-019-1839-z.
• [11] Identification of Novel Potentially Pleiotropic Variants Associated With Osteoporosis and Obesity Using the cFDR Method.J Clin Endocrinol Metab. 2018 Jan 1;103(1):125-138. doi: 10.1210/jc.2017-01531.
• [12] 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.
• [13] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [14] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [15] 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.
• [16] 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.
• [17] Multi-level gene expression profiles affected by thymidylate synthase and 5-fluorouracil in colon cancer. BMC Genomics. 2006 Apr 3;7:68. doi: 10.1186/1471-2164-7-68.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [19] 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.
• [20] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.