Details of Drug Off-Target (DOT)

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

• DOT Name: Metal regulatory transcription factor 1 (MTF1)
• Synonyms: MRE-binding transcription factor; Transcription factor MTF-1
• Gene Name: MTF1
• Related Disease: Intellectual disability, autosomal dominant 40
• UniProt ID: MTF1_HUMAN
• Pfam ID: PF00096
• Sequence:
  MGEHSPDNNIIYFEAEEDELTPDDKMLRFVDKNGLVPSSSGTVYDRTTVLIEQDPGTLED
  EDDDGQCGEHLPFLVGGEEGFHLIDHEAMSQGYVQHIISPDQIHLTINPGSTPMPRNIEG
  ATLTLQSECPETKRKEVKRYQCTFEGCPRTYSTAGNLRTHQKTHRGEYTFVCNQEGCGKA
  FLTSYSLRIHVRVHTKEKPFECDVQGCEKAFNTLYRLKAHQRLHTGKTFNCESEGCSKYF
  TTLSDLRKHIRTHTGEKPFRCDHDGCGKAFAASHHLKTHVRTHTGERPFFCPSNGCEKTF
  STQYSLKSHMKGHDNKGHSYNALPQHNGSEDTNHSLCLSDLSLLSTDSELRENSSTTQGQ
  DLSTISPAIIFESMFQNSDDTAIQEDPQQTASLTESFNGDAESVSDVPPSTGNSASLSLP
  LVLQPGLSEPPQPLLPASAPSAPPPAPSLGPGSQQAAFGNPPALLQPPEVPVPHSTQFAA
  NHQEFLPHPQAPQPIVPGLSVVAGASASAAAVASAVAAPAPPQSTTEPLPAMVQTLPLGA
  NSVLTNNPTITITPTPNTAILQSSLVMGEQNLQWILNGATSSPQNQEQIQQASKVEKVFF
  TTAVPVASSPGSSVQQIGLSVPVIIIKQEEACQCQCACRDSAKERASSRRKGCSSPPPPE
  PSPQAPDGPSLQLPAQTFSSAPVPGSSSSTLPSSCEQSRQAETPSDPQTETLSAMDVSEF
  LSLQSLDTPSNLIPIEALLQGEEEMGLTSSFSK
• Function: Zinc-dependent transcriptional regulator of cellular adaption to conditions of exposure to heavy metals. Binds to metal responsive elements (MRE) in promoters and activates the transcription of metallothionein genes like metallothionein-2/MT2A. Also regulates the expression of metalloproteases in response to intracellular zinc and functions as a catabolic regulator of cartilages.
• Reactome Pathway:
  Activation of gene expression by SREBF (SREBP) (R-HSA-2426168)
  MTF1 activates gene expression (R-HSA-5660489)
  PPARA activates gene expression (R-HSA-1989781)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability, autosomal dominant 40	DISAI0IH	Limited	Autosomal dominant	[1]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Metal regulatory transcription factor 1 (MTF1) affects the response to substance of Arsenic trioxide.	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Metal regulatory transcription factor 1 (MTF1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Metal regulatory transcription factor 1 (MTF1).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Metal regulatory transcription factor 1 (MTF1).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Metal regulatory transcription factor 1 (MTF1).	[5]
Busulfan	DMXYJ9C	Approved	Busulfan decreases the expression of Metal regulatory transcription factor 1 (MTF1).	[6]
Gallium nitrate	DMF9O6B	Approved	Gallium nitrate increases the expression of Metal regulatory transcription factor 1 (MTF1).	[7]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Metal regulatory transcription factor 1 (MTF1).	[8]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Metal regulatory transcription factor 1 (MTF1).	[9]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone decreases the expression of Metal regulatory transcription factor 1 (MTF1).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the activity of Metal regulatory transcription factor 1 (MTF1).	[11]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Metal regulatory transcription factor 1 (MTF1).	[12]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of Metal regulatory transcription factor 1 (MTF1).	[6]
BADGE	DMCK5DG	Investigative	BADGE increases the activity of Metal regulatory transcription factor 1 (MTF1).	[11]

2 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 Metal regulatory transcription factor 1 (MTF1).	[10]
Lead acetate	DML0GZ2	Investigative	Lead acetate affects the phosphorylation of Metal regulatory transcription factor 1 (MTF1).	[13]

References

• [1] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [2] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [3] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [4] Extremely low copper concentrations affect gene expression profiles of human prostate epithelial cell lines. Chem Biol Interact. 2010 Oct 6;188(1):214-9.
• [5] 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.
• [6] Direct transcriptomic comparison of xenobiotic metabolism and toxicity pathway induction of airway epithelium models at an air-liquid interface generated from induced pluripotent stem cells and primary bronchial epithelial cells. Cell Biol Toxicol. 2023 Feb;39(1):1-18. doi: 10.1007/s10565-022-09726-0. Epub 2022 May 31.
• [7] Role of oxidative stress in the induction of metallothionein-2A and heme oxygenase-1 gene expression by the antineoplastic agent gallium nitrate in human lymphoma cells. Free Radic Biol Med. 2008 Sep 15;45(6):763-72.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] Interactive gene expression pattern in prostate cancer cells exposed to phenolic antioxidants. Life Sci. 2002 Mar 1;70(15):1821-39.
• [10] 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.
• [11] In vitro transcriptomic analyses reveal pathway perturbations, estrogenic activities, and potencies of data-poor BPA alternative chemicals. Toxicol Sci. 2023 Feb 17;191(2):266-275. doi: 10.1093/toxsci/kfac127.
• [12] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [13] Heavy metal-induced metallothionein expression is regulated by specific protein phosphatase 2A complexes. J Biol Chem. 2014 Aug 8;289(32):22413-26. doi: 10.1074/jbc.M114.548677. Epub 2014 Jun 24.
• [14] Functional Profiling Identifies Determinants of Arsenic Trioxide Cellular Toxicity. Toxicol Sci. 2019 May 1;169(1):108-121. doi: 10.1093/toxsci/kfz024.