Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTI4CYTF)

• DOT Name: AMSH-like protease (STAMBPL1)
• Synonyms: AMSH-LP; EC 3.4.19.-; STAM-binding protein-like 1
• Gene Name: STAMBPL1
• Related Disease:
  Gastric cancer
  Stomach cancer
  Adult T-cell leukemia/lymphoma
  Familial thoracic aortic aneurysm and aortic dissection
  Multisystemic smooth muscle dysfunction syndrome
  Nasopharyngeal carcinoma
  Prostate cancer
  Prostate carcinoma
  Renal carcinoma
  Renal cell carcinoma
  Aortic aneurysm, familial thoracic 6
  Lung cancer
  Lung carcinoma
• UniProt ID: STALP_HUMAN
• PDB ID: 2ZNR; 2ZNV; 7L97
• EC Number: 3.4.19.-
• Pfam ID: PF01398 ; PF08969
• Sequence:
  MDQPFTVNSLKKLAAMPDHTDVSLSPEERVRALSKLGCNITISEDITPRRYFRSGVEMER
  MASVYLEEGNLENAFVLYNKFITLFVEKLPNHRDYQQCAVPEKQDIMKKLKEIAFPRTDE
  LKNDLLKKYNVEYQEYLQSKNKYKAEILKKLEHQRLIEAERKRIAQMRQQQLESEQFLFF
  EDQLKKQELARGQMRSQQTSGLSEQIDGSALSCFSTHQNNSLLNVFADQPNKSDATNYAS
  HSPPVNRALTPAATLSAVQNLVVEGLRCVVLPEDLCHKFLQLAESNTVRGIETCGILCGK
  LTHNEFTITHVIVPKQSAGPDYCDMENVEELFNVQDQHDLLTLGWIHTHPTQTAFLSSVD
  LHTHCSYQLMLPEAIAIVCSPKHKDTGIFRLTNAGMLEVSACKKKGFHPHTKEPRLFSIC
  KHVLVKDIKIIVLDLR
• Function: Zinc metalloprotease that specifically cleaves 'Lys-63'-linked polyubiquitin chains. Acts as a positive regulator of the TORC1 signaling pathway by mediating 'Lys-63'-linked deubiquitination of SESN2, thereby inhibiting SESN2-interaction with the GATOR2 complex. Does not cleave 'Lys-48'-linked polyubiquitin chains.
• Tissue Specificity: Ubiquitously expressed.
• Reactome Pathway: Metalloprotease DUBs (R-HSA-5689901)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Gastric cancer	DISXGOUK	Definitive	Biomarker	[1]
Stomach cancer	DISKIJSX	Definitive	Biomarker	[1]
Adult T-cell leukemia/lymphoma	DIS882XU	Strong	Biomarker	[2]
Familial thoracic aortic aneurysm and aortic dissection	DIS069FB	Strong	CausalMutation	[3]
Multisystemic smooth muscle dysfunction syndrome	DISV2K69	Strong	CausalMutation	[3]
Nasopharyngeal carcinoma	DISAOTQ0	Strong	Genetic Variation	[4]
Prostate cancer	DISF190Y	Strong	Biomarker	[5]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[5]
Renal carcinoma	DISER9XT	Strong	Altered Expression	[6]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[6]
Aortic aneurysm, familial thoracic 6	DISNTSXF	moderate	CausalMutation	[7]
Lung cancer	DISCM4YA	Limited	Genetic Variation	[8]
Lung carcinoma	DISTR26C	Limited	Genetic Variation	[8]

19 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 AMSH-like protease (STAMBPL1).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of AMSH-like protease (STAMBPL1).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of AMSH-like protease (STAMBPL1).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of AMSH-like protease (STAMBPL1).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of AMSH-like protease (STAMBPL1).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of AMSH-like protease (STAMBPL1).	[14]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of AMSH-like protease (STAMBPL1).	[15]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of AMSH-like protease (STAMBPL1).	[16]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of AMSH-like protease (STAMBPL1).	[17]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of AMSH-like protease (STAMBPL1).	[18]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of AMSH-like protease (STAMBPL1).	[19]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of AMSH-like protease (STAMBPL1).	[20]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of AMSH-like protease (STAMBPL1).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of AMSH-like protease (STAMBPL1).	[23]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of AMSH-like protease (STAMBPL1).	[24]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of AMSH-like protease (STAMBPL1).	[25]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of AMSH-like protease (STAMBPL1).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of AMSH-like protease (STAMBPL1).	[27]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of AMSH-like protease (STAMBPL1).	[28]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Camptothecin	DM6CHNJ	Phase 3	Camptothecin increases the methylation of AMSH-like protease (STAMBPL1).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of AMSH-like protease (STAMBPL1).	[26]

References

• [1] STAMBPL1 knockdown has antitumour effects on gastric cancer biological activities.Oncol Lett. 2019 Nov;18(5):4421-4428. doi: 10.3892/ol.2019.10789. Epub 2019 Sep 3.
• [2] An RNA interference screen identifies the Deubiquitinase STAMBPL1 as a critical regulator of human T-cell leukemia virus type 1 tax nuclear export and NF-B activation.J Virol. 2012 Mar;86(6):3357-69. doi: 10.1128/JVI.06456-11. Epub 2012 Jan 18.
• [3] Neonatal stroke and progressive leukoencephalopathy in a child with an ACTA2 mutation.J Child Neurol. 2013 Apr;28(4):531-4. doi: 10.1177/0883073812446631. Epub 2012 Jun 29.
• [4] A genome-wide association study of nasopharyngeal carcinoma identifies three new susceptibility loci.Nat Genet. 2010 Jul;42(7):599-603. doi: 10.1038/ng.601. Epub 2010 May 30.
• [5] Targeting the deubiquitinase STAMBPL1 triggers apoptosis in prostate cancer cells by promoting XIAP degradation.Cancer Lett. 2019 Aug 1;456:49-58. doi: 10.1016/j.canlet.2019.04.020. Epub 2019 Apr 17.
• [6] Cepharanthine Enhances TRAIL-Mediated Apoptosis Through STAMBPL1-Mediated Downregulation of Survivin Expression in Renal Carcinoma Cells.Int J Mol Sci. 2018 Oct 22;19(10):3280. doi: 10.3390/ijms19103280.
• [7] Cerebral arteriopathy associated with heterozygous Arg179Cys mutation in the ACTA2 gene: Report in 2 newborn siblings.Brain Dev. 2017 Jan;39(1):62-66. doi: 10.1016/j.braindev.2016.08.003. Epub 2016 Aug 25.
• [8] Deciphering the impact of common genetic variation on lung cancer risk: a genome-wide association study.Cancer Res. 2009 Aug 15;69(16):6633-41. doi: 10.1158/0008-5472.CAN-09-0680. Epub 2009 Aug 4.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] 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.
• [11] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [12] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [13] 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.
• [14] 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.
• [15] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [16] 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.
• [17] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [18] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [19] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] 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.
• [22] Reduced camptothecin sensitivity of estrogen receptor-positive human breast cancer cells following exposure to di(2-ethylhexyl)phthalate (DEHP) is associated with DNA methylation changes. Environ Toxicol. 2019 Apr;34(4):401-414.
• [23] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [24] Synergistic effect of JQ1 and rapamycin for treatment of human osteosarcoma. Int J Cancer. 2015 May 1;136(9):2055-64.
• [25] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [26] 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.
• [27] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [28] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.