Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBCA105)

• DOT Name: Transcription factor MafA (MAFA)
• Synonyms: Pancreatic beta-cell-specific transcriptional activator; RIPE3b1 factor; V-maf musculoaponeurotic fibrosarcoma oncogene homolog A
• Gene Name: MAFA
• Related Disease:
  Islet cell adenomatosis
  Maturity-onset diabetes of the young
  Non-insulin dependent diabetes
  Hyperglycemia
  Type-1 diabetes
  Type-1/2 diabetes
• UniProt ID: MAFA_HUMAN
• PDB ID: 4EOT
• Pfam ID: PF03131 ; PF08383
• Sequence:
  MAAELAMGAELPSSPLAIEYVNDFDLMKFEVKKEPPEAERFCHRLPPGSLSSTPLSTPCS
  SVPSSPSFCAPSPGTGGGGGAGGGGGSSQAGGAPGPPSGGPGAVGGTSGKPALEDLYWMS
  GYQHHLNPEALNLTPEDAVEALIGSGHHGAHHGAHHPAAAAAYEAFRGPGFAGGGGADDM
  GAGHHHGAHHAAHHHHAAHHHHHHHHHHGGAGHGGGAGHHVRLEERFSDDQLVSMSVREL
  NRQLRGFSKEEVIRLKQKRRTLKNRGYAQSCRFKRVQQRHILESEKCQLQSQVEQLKLEV
  GRLAKERDLYKEKYEKLAGRGGPGSAGGAGFPREPSPPQAGPGGAKGTADFFL
• Function: Transcription factor that activates insulin gene expression. Acts synergistically with NEUROD1/BETA2 and PDX1. Binds the insulin enhancer C1/RIPE3b element. Binds to consensus TRE-type MARE 5'-TGCTGACTCAGCA-3' DNA sequence.
• Tissue Specificity: Expressed in the islets of Langerhans (at protein level).
• KEGG Pathway:
  Type II diabetes mellitus (hsa04930)
  Maturity onset diabetes of the young (hsa04950)
• Reactome Pathway: Regulation of gene expression in beta cells (R-HSA-210745)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Islet cell adenomatosis	DISYT3QM	Strong	Genetic Variation	[1]
Maturity-onset diabetes of the young	DISG75M5	Strong	Biomarker	[2]
Non-insulin dependent diabetes	DISK1O5Z	moderate	Altered Expression	[3]
Hyperglycemia	DIS0BZB5	Limited	Altered Expression	[4]
Type-1 diabetes	DIS7HLUB	Limited	Genetic Variation	[5]
Type-1/2 diabetes	DISIUHAP	Limited	Altered Expression	[6]

3 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 Transcription factor MafA (MAFA).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Transcription factor MafA (MAFA).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Transcription factor MafA (MAFA).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Transcription factor MafA (MAFA).	[8]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Transcription factor MafA (MAFA).	[9]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 increases the expression of Transcription factor MafA (MAFA).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Transcription factor MafA (MAFA).	[12]
Mivebresib	DMCPF90	Phase 1	Mivebresib increases the expression of Transcription factor MafA (MAFA).	[10]
Harmine	DMPA5WD	Patented	Harmine increases the expression of Transcription factor MafA (MAFA).	[13]
Tributylstannanyl	DMHN7CB	Investigative	Tributylstannanyl decreases the expression of Transcription factor MafA (MAFA).	[15]

References

• [1] MAFA missense mutation causes familial insulinomatosis and diabetes mellitus.Proc Natl Acad Sci U S A. 2018 Jan 30;115(5):1027-1032. doi: 10.1073/pnas.1712262115. Epub 2018 Jan 16.
• [2] MafA is a key regulator of glucose-stimulated insulin secretion.Mol Cell Biol. 2005 Jun;25(12):4969-76. doi: 10.1128/MCB.25.12.4969-4976.2005.
• [3] Variability in endocrine cell identity in patients with chronic pancreatitis undergoing islet autotransplantation.Am J Transplant. 2019 May;19(5):1568-1576. doi: 10.1111/ajt.15154. Epub 2018 Nov 28.
• [4] Inactivation of specific cell transcription factors in type 2 diabetes.J Clin Invest. 2013 Aug;123(8):3305-16. doi: 10.1172/JCI65390. Epub 2013 Jul 1.
• [5] Insulin transactivator MafA regulates intrathymic expression of insulin and affects susceptibility to type 1 diabetes.Diabetes. 2010 Oct;59(10):2579-87. doi: 10.2337/db10-0476. Epub 2010 Aug 3.
• [6] Thioredoxin-interacting protein regulates insulin transcription through microRNA-204.Nat Med. 2013 Sep;19(9):1141-6. doi: 10.1038/nm.3287. Epub 2013 Aug 25.
• [7] 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.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [11] 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.
• [12] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [13] A high-throughput chemical screen reveals that harmine-mediated inhibition of DYRK1A increases human pancreatic beta cell replication. Nat Med. 2015 Apr;21(4):383-8. doi: 10.1038/nm.3820. Epub 2015 Mar 9.
• [14] 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.
• [15] In Vitro Assays to Identify Metabolism-Disrupting Chemicals with Diabetogenic Activity in a Human Pancreatic -Cell Model. Int J Mol Sci. 2022 May 1;23(9):5040. doi: 10.3390/ijms23095040.