PDX1

Pancreatic and duodenal homeobox 1
PDB rendering based on 2h1k.
Available structures PDB 2h1k
Identifiers
Symbols	PDX1; GSF; IDX-1; IPF1; IUF1; MODY4; PDX-1; STF-1
External IDs	OMIM: 600733 MGI: 102851 HomoloGene: 175 GeneCards: PDX1 Gene
Gene Ontology Molecular function • chromatin binding • sequence-specific DNA binding transcription factor activity • sequence-specific DNA binding Cellular component • nucleus • intracellular part Biological process • negative regulation of transcription from RNA polymerase II promoter • type B pancreatic cell differentiation • glucose metabolic process • generation of precursor metabolites and energy • regulation of transcription, DNA-dependent • transcription from RNA polymerase II promoter • nitric oxide mediated signal transduction • multicellular organismal development • positive regulation of cell proliferation • negative regulation of cell proliferation • organ morphogenesis • morphogenesis of embryonic epithelium • insulin secretion • exocrine pancreas development • endocrine pancreas development • glucose homeostasis • positive regulation of transcription from RNA polymerase II promoter • detection of glucose Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	3651	18609
Ensembl	ENSG00000139515	ENSMUSG00000029644
UniProt	P52945	Q3ZB03
RefSeq (mRNA)	NM_000209.3	NM_008814.3
RefSeq (protein)	NP_000200.1	NP_032840.1
Location (UCSC)	Chr 13: 28.49 – 28.5 Mb	Chr 5: 148.08 – 148.09 Mb
PubMed search	[1]	[2]

Pdx1 (Pancreatic and duodenal homeobox 1), also known as insulin promoter factor 1, is a transcription factor necessary for pancreatic development and β-cell maturation. Pdx1 (in rodents), otherwise known as Ipf1 (in humans), is the gene encoding it.^[1]

Function

Pancreatic development

In embryonic development, Pdx1 is expressed by a population of cells in the posterior foregut region of the definitive endoderm, and Pdx1⁺ epithelial cells give rise to the developing pancreatic buds, and eventually, the whole of the pancreas—its exocrine, endocrine, and ductal cell populations.^[2] Pancreatic Pdx1⁺ cells first arise at mouse embryonic day 8.5-9.0 (E8.5-9.0), and Pdx1 expression continues until E12.0-E12.5,^[3] after which Pdx1 expression decreases and the pancreas is formed—other transcription factors are expressed, controlling the fates of the cells of the newly formed pancreas.^[4] Homozygous Pdx1 knockout mice form pancreatic buds but fail to develop a pancreas,^[4] and transgenic mice in which tetracycline application results in death of Pdx1⁺ cells are almost completely apancreatic if doxycycline (tetracycline derivative) is administered throughout the pregnancy of these transgenic mice, illustrating the necessity of Pdx1⁺ cells in pancreatic development.^[3]

β-cell Maturation

Pdx1 is also necessary for β-cell maturation: developing β-cells co-express Pdx1, Nkx6-1, and insulin, a process that results in the silencing of MafB and the expression of MafA, a necessary switch in maturation of β-cells.^[2] Pdx1 appears to also play a role in the fating of endocrine cells, encoding for insulin and somatostatin, two pancreatic endocrine products, while repressing glucagon. Thus, Pdx1 expression apparently favors the production of insulin⁺ β-cells and somatostatin⁺Δ-cells rather than glucagon⁺ α-cells.

Transcriptional Network

Pdx1⁺ pancreatic progenitor cells also co-express Hlxb9, Hnf6, Ptf1a and Nkx6-1, and these progenitor cells form the initial pancreatic buds, which further proliferate and branch in response to FGF-10 signaling. Afterwards, fating of the pancreatic cells begins; a population of cells has Notch signaling inhibited, and subsequently, expresses Ngn3. This Ngn3⁺ population is a transient population of pancreatic endocrine progenitors that gives rise to the α, β, Δ, PP, and ε cells of the Islets of Langerhans.^[3] Other cells will give rise to the exocrine and ductal pancreatic cell populations.

Pathology

Mutations in the Pdx1 gene may be involved in several pancreatic pathologies, possibly diabetes mellitus.^[5]

Interactions

Pdx1 has been shown to interact with MAFA.^[6]

References

1. ^ Stoffel M, Stein R, Wright CV, Espinosa R, Le Beau MM, Bell GI (July 1995). "Localization of human homeodomain transcription factor insulin promoter factor 1 (IPF1) to chromosome band 13q12.1". Genomics 28 (1): 125–6. doi:10.1006/geno.1995.1120. PMID 7590740. 
2. ^ ^{a b} D'Amour KA, Bang AG, Eliazer S, Kelly OG, Agulnick AD, Smart NG, Moorman MA, Kroon E, Carpenter MK, Baetge EE (November 2006). "Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells". Nat. Biotechnol. 24 (11): 1392–401. doi:10.1038/nbt1259. PMID 17053790. 
3. ^ ^{a b c} Stanger BZ, Tanaka AJ, Melton DA (February 2007). "Organ size is limited by the number of embryonic progenitor cells in the pancreas but not the liver". Nature 445 (7130): 886–91. doi:10.1038/nature05537. PMID 17259975. 
4. ^ ^{a b} Liew CG, Shah NN, Briston SJ, Shepherd RM, Khoo CP, Dunne MJ, Moore HD, Cosgrove KE, Andrews PW (2008). "PAX4 enhances beta-cell differentiation of human embryonic stem cells". PLoS ONE 3 (3): e1783. doi:10.1371/journal.pone.0001783. PMC 2262135. PMID 18335054. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2262135. 
5. ^ "Entrez Gene: PDX1 pancreatic and duodenal homeobox 1". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3651. 
6. ^ Zhao, Li; Guo Min, Matsuoka Taka-Aki, Hagman Derek K, Parazzoli Susan D, Poitout Vincent, Stein Roland (Mar. 2005). "The islet beta cell-enriched MafA activator is a key regulator of insulin gene transcription". J. Biol. Chem. (United States) 280 (12): 11887–94. doi:10.1074/jbc.M409475200. ISSN 0021-9258. PMID 15665000. 

Further reading

• Zhou Q, Brown J, Kanarek A, Rajagopal J, & Douglas A. Melton DA (2008). "In vivo reprogramming of adult pancreatic exocrine cells to β-cells". Nature 454 (7209): 627–32. doi:10.1038/nature07314. PMID 18754011. 
• Hui H, Perfetti R (2002). "Pancreas duodenum homeobox-1 regulates pancreas development during embryogenesis and islet cell function in adulthood.". Eur. J. Endocrinol. 146 (2): 129–41. doi:10.1530/eje.0.1460129. PMID 11834421. 
• Leonard J, Peers B, Johnson T, et al. (1994). "Characterization of somatostatin transactivating factor-1, a novel homeobox factor that stimulates somatostatin expression in pancreatic islet cells.". Mol. Endocrinol. 7 (10): 1275–83. doi:10.1210/me.7.10.1275. PMID 7505393. 
• Stoffel M, Stein R, Wright CV, et al. (1995). "Localization of human homeodomain transcription factor insulin promoter factor 1 (IPF1) to chromosome band 13q12.1.". Genomics 28 (1): 125–6. doi:10.1006/geno.1995.1120. PMID 7590740. 
• Inoue H, Riggs AC, Tanizawa Y, et al. (1996). "Isolation, characterization, and chromosomal mapping of the human insulin promoter factor 1 (IPF-1) gene.". Diabetes 45 (6): 789–94. doi:10.2337/diabetes.45.6.789. PMID 8635654. 
• Waeber G, Thompson N, Nicod P, Bonny C (1997). "Transcriptional activation of the GLUT2 gene by the IPF-1/STF-1/IDX-1 homeobox factor.". Mol. Endocrinol. 10 (11): 1327–34. doi:10.1210/me.10.11.1327. PMID 8923459. 
• Watada H, Kajimoto Y, Kaneto H, et al. (1997). "Involvement of the homeodomain-containing transcription factor PDX-1 in islet amyloid polypeptide gene transcription.". Biochem. Biophys. Res. Commun. 229 (3): 746–51. doi:10.1006/bbrc.1996.1875. PMID 8954967. 
• Marshak S, Totary H, Cerasi E, Melloul D (1997). "Purification of the beta-cell glucose-sensitive factor that transactivates the insulin gene differentially in normal and transformed islet cells.". Proc. Natl. Acad. Sci. U.S.A. 93 (26): 15057–62. doi:10.1073/pnas.93.26.15057. PMC 26355. PMID 8986763. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=26355. 
• Stoffers DA, Zinkin NT, Stanojevic V, et al. (1997). "Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence.". Nat. Genet. 15 (1): 106–10. doi:10.1038/ng0197-106. PMID 8988180. 
• Sharma S, Jhala US, Johnson T, et al. (1997). "Hormonal regulation of an islet-specific enhancer in the pancreatic homeobox gene STF-1.". Mol. Cell. Biol. 17 (5): 2598–604. PMC 232109. PMID 9111329. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=232109. 
• Carty MD, Lillquist JS, Peshavaria M, et al. (1997). "Identification of cis- and trans-active factors regulating human islet amyloid polypeptide gene expression in pancreatic beta-cells.". J. Biol. Chem. 272 (18): 11986–93. doi:10.1074/jbc.272.18.11986. PMID 9115263. 
• Macfarlane WM, Smith SB, James RF, et al. (1997). "The p38/reactivating kinase mitogen-activated protein kinase cascade mediates the activation of the transcription factor insulin upstream factor 1 and insulin gene transcription by high glucose in pancreatic beta-cells.". J. Biol. Chem. 272 (33): 20936–44. doi:10.1074/jbc.272.33.20936. PMID 9252422. 
• Macfarlane WM, Frayling TM, Ellard S, et al. (1999). "Missense mutations in the insulin promoter factor-1 gene predispose to type 2 diabetes.". J. Clin. Invest. 104 (9): R33–9. doi:10.1172/JCI7449. PMC 481047. PMID 10545530. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=481047. 
• Hani EH, Stoffers DA, Chèvre JC, et al. (1999). "Defective mutations in the insulin promoter factor-1 (IPF-1) gene in late-onset type 2 diabetes mellitus.". J. Clin. Invest. 104 (9): R41–8. doi:10.1172/JCI7469. PMC 409821. PMID 10545531. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=409821. 
• Glick E, Leshkowitz D, Walker MD (2000). "Transcription factor BETA2 acts cooperatively with E2A and PDX1 to activate the insulin gene promoter.". J. Biol. Chem. 275 (3): 2199–204. doi:10.1074/jbc.275.3.2199. PMID 10636926. 
• Schwartz PT, Perez-Villamil B, Rivera A, et al. (2000). "Pancreatic homeodomain transcription factor IDX1/IPF1 expressed in developing brain regulates somatostatin gene transcription in embryonic neural cells.". J. Biol. Chem. 275 (25): 19106–14. doi:10.1074/jbc.M000655200. PMID 10751390. 
• Hartley JL, Temple GF, Brasch MA (2001). "DNA cloning using in vitro site-specific recombination.". Genome Res. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=310948. 
• Liu Y, MacDonald RJ, Swift GH (2001). "DNA binding and transcriptional activation by a PDX1.PBX1b.MEIS2b trimer and cooperation with a pancreas-specific basic helix-loop-helix complex.". J. Biol. Chem. 276 (21): 17985–93. doi:10.1074/jbc.M100678200. PMID 11279116. 
• Samaras SE, Cissell MA, Gerrish K, et al. (2002). "Conserved sequences in a tissue-specific regulatory region of the pdx-1 gene mediate transcription in Pancreatic beta cells: role for hepatocyte nuclear factor 3 beta and Pax6.". Mol. Cell. Biol. 22 (13): 4702–13. doi:10.1128/MCB.22.13.4702-4713.2002. PMC 133887. PMID 12052878. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=133887. 
• Zhou J, Pineyro MA, Wang X, et al. (2002). "Exendin-4 differentiation of a human pancreatic duct cell line into endocrine cells: involvement of PDX-1 and HNF3beta transcription factors.". J. Cell. Physiol. 192 (3): 304–14. doi:10.1002/jcp.10143. PMID 12124776. 

External links

• GeneReviews/NCBI/NIH/UW entry on Permanent Neonatal Diabetes Mellitus
• MeSH PDX1+protein,+human

This article incorporates text from the United States National Library of Medicine, which is in the public domain.