Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7SWA57)

• DOT Name: Pancreas transcription factor 1 subunit alpha (PTF1A)
• Synonyms: Class A basic helix-loop-helix protein 29; bHLHa29; Pancreas-specific transcription factor 1a; bHLH transcription factor p48; p48 DNA-binding subunit of transcription factor PTF1; PTF1-p48
• Gene Name: PTF1A
• Related Disease:
  Adult glioblastoma
  Breast carcinoma
  Glioma
  Permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome
  Advanced cancer
  Alzheimer disease
  Cerebellar disorder
  DEND syndrome
  Hepatitis C virus infection
  Influenza
  Matthew-Wood syndrome
  Neoplasm
  Pancreatic agenesis 2
  Pancreatic ductal carcinoma
  Pancreatic tumour
  Patent ductus arteriosus
  Permanent neonatal diabetes mellitus
  Promyelocytic leukaemia
  Transitional cell carcinoma
  Type-1/2 diabetes
  Vibrio cholerae infection
  Glioblastoma multiforme
  Pancreatic agenesis
  Neonatal diabetes mellitus
  Non-insulin dependent diabetes
  Xeroderma pigmentosum
• UniProt ID: PTF1A_HUMAN
• Pfam ID: PF00010
• Sequence:
  MDAVLLEHFPGGLDAFPSSYFDEDDFFTDQSSRDPLEDGDELLADEQAEVEFLSHQLHEY
  CYRDGACLLLQPAPPAAPLALAPPSSGGLGEPDDGGGGGYCCETGAPPGGFPYSPGSPPS
  CLAYPCAGAAVLSPGARLRGLSGAAAAAARRRRRVRSEAELQQLRQAANVRERRRMQSIN
  DAFEGLRSHIPTLPYEKRLSKVDTLRLAIGYINFLSELVQADLPLRGGGAGGCGGPGGGG
  RLGGDSPGSQAQKVIICHRGTRSPSPSDPDYGLPPLAGHSLSWTDEKQLKEQNIIRTAKV
  WTPEDPRKLNSKSSFNNIENEPPFEFVS
• Function: Transcription factor implicated in the cell fate determination in various organs. Binds to the E-box consensus sequence 5'-CANNTG-3'. Plays a role in early and late pancreas development and differentiation. Important for determining whether cells allocated to the pancreatic buds continue towards pancreatic organogenesis or revert back to duodenal fates. May be involved in the maintenance of exocrine pancreas-specific gene expression including ELA1 and amylase. Required for the formation of pancreatic acinar and ductal cells. Plays an important role in cerebellar development. Directly regulated by FOXN4 and RORC during retinal development, FOXN4-PTF1A pathway plays a central role in directing the differentiation of retinal progenitors towards horizontal and amacrine fates.
• Tissue Specificity: Pancreas-specific (at protein level). Loss of expression is seen in ductal type pancreas cancers.
• Reactome Pathway: Regulation of gene expression in early pancreatic precursor cells (R-HSA-210747)

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Definitive	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Definitive	Biomarker	[1]
Glioma	DIS5RPEH	Definitive	Biomarker	[2]
Permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome	DIS4HC21	Definitive	Autosomal recessive	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Alzheimer disease	DISF8S70	Strong	Biomarker	[5]
Cerebellar disorder	DIS2O7WM	Strong	Biomarker	[6]
DEND syndrome	DISRNWGB	Strong	Genetic Variation	[7]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[8]
Influenza	DIS3PNU3	Strong	Biomarker	[9]
Matthew-Wood syndrome	DISA7HR7	Strong	Genetic Variation	[10]
Neoplasm	DISZKGEW	Strong	Altered Expression	[11]
Pancreatic agenesis 2	DIS18YEZ	Strong	Autosomal recessive	[12]
Pancreatic ductal carcinoma	DIS26F9Q	Strong	Altered Expression	[11]
Pancreatic tumour	DIS3U0LK	Strong	Genetic Variation	[13]
Patent ductus arteriosus	DIS9P8YS	Strong	Genetic Variation	[13]
Permanent neonatal diabetes mellitus	DIS5AEXS	Strong	Autosomal recessive	[12]
Promyelocytic leukaemia	DISYGG13	Strong	Biomarker	[14]
Transitional cell carcinoma	DISWVVDR	Strong	Altered Expression	[15]
Type-1/2 diabetes	DISIUHAP	Strong	Genetic Variation	[16]
Vibrio cholerae infection	DISW7E3U	Strong	Biomarker	[17]
Glioblastoma multiforme	DISK8246	moderate	Altered Expression	[1]
Pancreatic agenesis	DISTVEYC	Supportive	Autosomal recessive	[18]
Neonatal diabetes mellitus	DISFHF9K	Limited	Genetic Variation	[19]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[20]
Xeroderma pigmentosum	DISQ9H19	Limited	Genetic Variation	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Folic acid	DMEMBJC	Approved	Folic acid increases the expression of Pancreas transcription factor 1 subunit alpha (PTF1A).	[22]

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 Pancreas transcription factor 1 subunit alpha (PTF1A).	[23]

References

• [1] EBP1 protein modulates the expression of human MHC class II molecules in non-hematopoietic cancer cells.Int J Oncol. 2015 Aug;47(2):481-9. doi: 10.3892/ijo.2015.3051. Epub 2015 Jun 16.
• [2] Negative regulation of p53 by the long isoform of ErbB3 binding protein Ebp1 in brain tumors.Cancer Res. 2010 Dec 1;70(23):9730-41. doi: 10.1158/0008-5472.CAN-10-1882. Epub 2010 Nov 23.
• [3] A novel PTF1A mutation in a patient with severe pancreatic and cerebellar involvement. Clin Genet. 2011 Aug;80(2):196-8. doi: 10.1111/j.1399-0004.2010.01613.x.
• [4] The discovery of potent and stable short peptide FGFR1 antagonist for cancer therapy.Eur J Pharm Sci. 2020 Feb 15;143:105179. doi: 10.1016/j.ejps.2019.105179. Epub 2019 Dec 10.
• [5] Direct reprogramming of fibroblasts into neural stem cells by single non-neural progenitor transcription factor Ptf1a.Nat Commun. 2018 Jul 20;9(1):2865. doi: 10.1038/s41467-018-05209-1.
• [6] A Turkish newborn infant with cerebellar agenesis/neonatal diabetes mellitus and PTF1A mutation.Genet Couns. 2009;20(2):147-52.
• [7] Neonatal Diabetes: Two Cases with Isolated Pancreas Agenesis due to Homozygous PTF1A Enhancer Mutations and One with Developmental Delay, Epilepsy, and Neonatal Diabetes Syndrome due to KCNJ11 Mutation.J Clin Res Pediatr Endocrinol. 2018 Jun 1;10(2):168-174. doi: 10.4274/jcrpe.5162. Epub 2017 Sep 25.
• [8] Modulation of HCV replication and translation by ErbB3 binding protein1 isoforms.Virology. 2017 Jan;500:35-49. doi: 10.1016/j.virol.2016.10.006. Epub 2016 Oct 19.
• [9] Investigation of the potential of a 48 kDa protein as a vaccine candidate for infection against nontypable Haemophilus influenzae.Vaccine. 2007 May 16;25(20):4012-9. doi: 10.1016/j.vaccine.2007.02.048. Epub 2007 Mar 8.
• [10] A pipeline for rapidly generating genetically engineered mouse models of pancreatic cancer using in vivo CRISPR-Cas9-mediated somatic recombination.Lab Invest. 2019 Jul;99(8):1233-1244. doi: 10.1038/s41374-018-0171-z. Epub 2019 Feb 6.
• [11] Induced PTF1a expression in pancreatic ductal adenocarcinoma cells activates acinar gene networks, reduces tumorigenic properties, and sensitizes cells to gemcitabine treatment.Mol Oncol. 2018 Jun;12(7):1104-1124. doi: 10.1002/1878-0261.12314. Epub 2018 May 21.
• [12] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [13] PI3K regulation of RAC1 is required for KRAS-induced pancreatic tumorigenesis in mice.Gastroenterology. 2014 Dec;147(6):1405-16.e7. doi: 10.1053/j.gastro.2014.08.032. Epub 2014 Aug 27.
• [14] Induction of leukemia cell differentiation and apoptosis by recombinant P48, a modulin derived from Mycoplasma fermentans.Biochem Biophys Res Commun. 2000 Mar 5;269(1):284-9. doi: 10.1006/bbrc.2000.2282.
• [15] Impaired alpha-interferon signaling in transitional cell carcinoma: lack of p48 expression in 5637 cells.Cancer Res. 2001 Mar 1;61(5):2261-6.
• [16] Variable Phenotype of Diabetes Mellitus in Siblings with a Homozygous PTF1A Enhancer Mutation.Horm Res Paediatr. 2015;84(3):206-11. doi: 10.1159/000435782. Epub 2015 Jul 14.
• [17] Construction of a fusion anti-caries DNA vaccine in transgenic tomato plants for PAcA gene and cholera toxin B subunit.Biotechnol Appl Biochem. 2019 Nov;66(6):924-929. doi: 10.1002/bab.1806. Epub 2019 Dec 5.
• [18] Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis. Nat Genet. 2014 Jan;46(1):61-64. doi: 10.1038/ng.2826. Epub 2013 Nov 10.
• [19] Clinical characteristics and molecular genetic analysis of 22 patients with neonatal diabetes from the South-Eastern region of Turkey: predominance of non-KATP channel mutations.Eur J Endocrinol. 2015 Jun;172(6):697-705. doi: 10.1530/EJE-14-0852. Epub 2015 Mar 9.
• [20] Functional and association analysis of an Amerindian-derived population-specific p.(Thr280Met) variant in RBPJL, a component of the PTF1 complex.Eur J Hum Genet. 2018 Feb;26(2):238-246. doi: 10.1038/s41431-017-0062-6. Epub 2018 Jan 4.
• [21] Xeroderma pigmentosum p48 gene enhances global genomic repair and suppresses UV-induced mutagenesis.Mol Cell. 2000 Apr;5(4):737-44. doi: 10.1016/s1097-2765(00)80252-x.
• [22] 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.
• [23] 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.