Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMPM1P5)

• DOT Name: Proteasome maturation protein (POMP)
• Synonyms: Proteassemblin; Protein UMP1 homolog; hUMP1; Voltage-gated K channel beta subunit 4.1
• Gene Name: POMP
• Related Disease:
  Autoimmune disease
  Breast cancer
  Keratosis
  Keratosis linearis-ichthyosis congenita-sclerosing keratoderma syndrome
  Myelodysplastic syndrome
  Neoplasm
  Proteasome-associated autoinflammatory syndrome 2
  Psoriasis
  Skin disease
  Advanced cancer
  Breast carcinoma
  Immunodeficiency
• UniProt ID: POMP_HUMAN
• Pfam ID: PF05348
• Sequence:
  MNARGLGSELKDSIPVTELSASGPFESHDLLRKGFSCVKNELLPSHPLELSEKNFQLNQD
  KMNFSTLRNIQGLFAPLKLQMEFKAVQQVQRLPFLSSSNLSLDVLRGNDETIGFEDILND
  PSQSEVMGEPHLMVEYKLGLL
• Function: Molecular chaperone essential for the assembly of standard proteasomes and immunoproteasomes. Degraded after completion of proteasome maturation. Mediates the association of 20S preproteasome with the endoplasmic reticulum.
• Tissue Specificity: Strongly expressed from the basal layer to the granular layer of healthy epidermis, whereas in KLICK patients there is a gradual decrease of expression toward the granular layer.
• KEGG Pathway: Proteasome (hsa03050)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autoimmune disease	DISORMTM	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Keratosis	DISF0NF1	Strong	Genetic Variation	[3]
Keratosis linearis-ichthyosis congenita-sclerosing keratoderma syndrome	DIS6O9UM	Strong	Autosomal recessive	[4]
Myelodysplastic syndrome	DISYHNUI	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Proteasome-associated autoinflammatory syndrome 2	DISPA7XW	Strong	Autosomal dominant	[6]
Psoriasis	DIS59VMN	Strong	Biomarker	[7]
Skin disease	DISDW8R6	Strong	Genetic Variation	[3]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[8]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[9]
Immunodeficiency	DIS093I0	moderate	Genetic Variation	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Proteasome maturation protein (POMP).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Proteasome maturation protein (POMP).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Proteasome maturation protein (POMP).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Proteasome maturation protein (POMP).	[13]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Proteasome maturation protein (POMP).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Proteasome maturation protein (POMP).	[16]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Proteasome maturation protein (POMP).	[17]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Proteasome maturation protein (POMP).	[18]

1 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 Proteasome maturation protein (POMP).	[15]

References

• [1] Heterozygous Truncating Variants in POMP Escape Nonsense-Mediated Decay and Cause a Unique Immune Dysregulatory Syndrome.Am J Hum Genet. 2018 Jun 7;102(6):1126-1142. doi: 10.1016/j.ajhg.2018.04.010. Epub 2018 May 24.
• [2] MicroRNA-101 Suppresses Tumor Cell Proliferation by Acting as an Endogenous Proteasome Inhibitor via Targeting the Proteasome Assembly Factor POMP.Mol Cell. 2015 Jul 16;59(2):243-57. doi: 10.1016/j.molcel.2015.05.036. Epub 2015 Jul 2.
• [3] siRNA silencing of proteasome maturation protein (POMP) activates the unfolded protein response and constitutes a model for KLICK genodermatosis.PLoS One. 2012;7(1):e29471. doi: 10.1371/journal.pone.0029471. Epub 2012 Jan 3.
• [4] A single-nucleotide deletion in the POMP 5' UTR causes a transcriptional switch and altered epidermal proteasome distribution in KLICK genodermatosis. Am J Hum Genet. 2010 Apr 9;86(4):596-603. doi: 10.1016/j.ajhg.2010.02.018. Epub 2010 Mar 11.
• [5] MCM3AP and POMP Mutations Cause a DNA-Repair and DNA-Damage-Signaling Defect in an Immunodeficient Child.Hum Mutat. 2016 Mar;37(3):257-68. doi: 10.1002/humu.22939. Epub 2015 Dec 30.
• [6] Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production. J Clin Invest. 2015 Nov 2;125(11):4196-211. doi: 10.1172/JCI81260. Epub 2015 Oct 20.
• [7] The proteasome maturation protein POMP increases proteasome assembly and activity in psoriatic lesional skin.J Dermatol Sci. 2017 Oct;88(1):10-19. doi: 10.1016/j.jdermsci.2017.04.009. Epub 2017 Apr 30.
• [8] New addiction to the NRF2-related factor NRF3 in cancer cells: Ubiquitin-independent proteolysis through the 20S proteasome.Cancer Sci. 2020 Jan;111(1):6-14. doi: 10.1111/cas.14244. Epub 2019 Dec 14.
• [9] Genetic modifiers of menopausal hormone replacement therapy and breast cancer risk: a genome-wide interaction study.Endocr Relat Cancer. 2013 Nov 4;20(6):875-87. doi: 10.1530/ERC-13-0349. Print 2013 Dec.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] 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.
• [12] 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.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] 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.
• [15] 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.
• [16] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [17] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [18] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.