Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6Z5AHP)

• DOT Name: Dual specificity protein phosphatase 7 (DUSP7)
• Synonyms: EC 3.1.3.16; EC 3.1.3.48; Dual specificity protein phosphatase PYST2
• Gene Name: DUSP7
• Related Disease:
  Arthritis
  Acute leukaemia
  Acute lymphocytic leukaemia
  Acute monocytic leukemia
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Childhood acute lymphoblastic leukemia
  Estrogen-receptor positive breast cancer
  Myeloid leukaemia
  Acute myelogenous leukaemia
• UniProt ID: DUS7_HUMAN
• PDB ID: 4Y2E
• EC Number: 3.1.3.16; 3.1.3.48
• Pfam ID: PF00782 ; PF00581
• Sequence:
  MKNQLRGPPARAHMSTSGAAAAGGTRAGSEPGAGSGSGAGTGAGAATGAGAMPCKSAEWL
  QEELEARGGASLLLLDCRPHELFESSHIETAINLAIPGLMLRRLRKGNLPIRSIIPNHAD
  KERFATRCKAATVLLYDEATAEWQPEPGAPASVLGLLLQKLRDDGCQAYYLQGGFNKFQT
  EYSEHCETNVDSSSSPSSSPPTSVLGLGGLRISSDCSDGESDRELPSSATESDGSPVPSS
  QPAFPVQILPYLYLGCAKDSTNLDVLGKYGIKYILNVTPNLPNAFEHGGEFTYKQIPISD
  HWSQNLSQFFPEAISFIDEARSKKCGVLVHCLAGISRSVTVTVAYLMQKMNLSLNDAYDF
  VKRKKSNISPNFNFMGQLLDFERTLGLSSPCDNHASSEQLYFSTPTNHNLFPLNTLEST
• Function: Dual specificity protein phosphatase. Shows high activity towards MAPK1/ERK2. Also has lower activity towards MAPK14 and MAPK8. In arrested oocytes, plays a role in meiotic resumption. Promotes nuclear envelope breakdown and activation of the CDK1/Cyclin-B complex in oocytes, probably by dephosphorylating and inactivating the conventional protein kinase C (cPKC) isozyme PRKCB. May also inactivate PRKCA and/or PRKCG. Also important in oocytes for normal chromosome alignment on the metaphase plate and progression to anaphase, where it might regulate activity of the spindle-assembly checkpoint (SAC) complex.
• Tissue Specificity: Strongly expressed in liver . Expressed at significantly higher levels in malignant hematopoietic cells than in corresponding non-malignant cells .
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Efferocytosis (hsa04148)
• Reactome Pathway:
  ERKs are inactivated (R-HSA-202670)
  Negative regulation of MAPK pathway (R-HSA-5675221)
  Signaling by MAPK mutants (R-HSA-9652817)
  RAF-independent MAPK1/3 activation (R-HSA-112409)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arthritis	DIST1YEL	Definitive	Biomarker	[1]
Acute leukaemia	DISDQFDI	Strong	Biomarker	[2]
Acute lymphocytic leukaemia	DISPX75S	Strong	Altered Expression	[3]
Acute monocytic leukemia	DIS28NEL	Strong	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[4]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[4]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Altered Expression	[3]
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Altered Expression	[5]
Myeloid leukaemia	DISMN944	Strong	Altered Expression	[2]
Acute myelogenous leukaemia	DISCSPTN	Limited	Altered Expression	[2]

1 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 Dual specificity protein phosphatase 7 (DUSP7).	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Dual specificity protein phosphatase 7 (DUSP7).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Dual specificity protein phosphatase 7 (DUSP7).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Dual specificity protein phosphatase 7 (DUSP7).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Dual specificity protein phosphatase 7 (DUSP7).	[10]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Dual specificity protein phosphatase 7 (DUSP7).	[11]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Dual specificity protein phosphatase 7 (DUSP7).	[12]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Dual specificity protein phosphatase 7 (DUSP7).	[13]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Dual specificity protein phosphatase 7 (DUSP7).	[13]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Dual specificity protein phosphatase 7 (DUSP7).	[14]
Ampicillin	DMHWE7P	Approved	Ampicillin increases the expression of Dual specificity protein phosphatase 7 (DUSP7).	[15]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Dual specificity protein phosphatase 7 (DUSP7).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Dual specificity protein phosphatase 7 (DUSP7).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Dual specificity protein phosphatase 7 (DUSP7).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Dual specificity protein phosphatase 7 (DUSP7).	[19]

References

• [1] mRNA profiling identifies low levels of phosphatases dualspecific phosphatase? (DUSP7) and cell division cycle?5B (CDC25B) in patients with early arthritis.Clin Exp Immunol. 2017 Jul;189(1):113-119. doi: 10.1111/cei.12953. Epub 2017 Mar 28.
• [2] Overexpression of the dual-specificity MAPK phosphatase PYST2 in acute leukemia.Cancer Lett. 2003 Sep 25;199(2):185-92. doi: 10.1016/s0304-3835(03)00352-5.
• [3] Dual-specificity phosphatase Pyst2-L is constitutively highly expressed in myeloid leukemia and other malignant cells.Oncogene. 2003 Oct 23;22(48):7649-60. doi: 10.1038/sj.onc.1206971.
• [4] Long non-coding RNA MIAT promotes breast cancer progression and functions as ceRNA to regulate DUSP7 expression by sponging miR-155-5p.Oncotarget. 2017 Jul 12;8(44):76153-76164. doi: 10.18632/oncotarget.19190. eCollection 2017 Sep 29.
• [5] Linc-RoR promotes MAPK/ERK signaling and confers estrogen-independent growth of breast cancer.Mol Cancer. 2017 Oct 17;16(1):161. doi: 10.1186/s12943-017-0727-3.
• [6] 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.
• [7] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] 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.
• [11] 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.
• [12] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [13] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [14] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [15] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] 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.
• [18] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [19] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.