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PDX1  -  pancreatic and duodenal homeobox 1

Homo sapiens

 
 
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Disease relevance of PDX1

 

High impact information on PDX1

 

Chemical compound and disease context of PDX1

 

Biological context of PDX1

  • We identified five IPF1 variants, including one new missense mutation E224K, the previously described diabetes-associated duplication P242 P243dupP, two silent mutations in the codons for Leu54 (c.162G>A) and Ala256 (c.768C>A), and a substitution in the 5'-untranslated region (c.-18C>T) [13].
  • Direct sequence analysis of exons 1 and 2 of the IPF1 gene revealed two point mutations within the homeobox in exon 2 [14].
  • Localization of human homeodomain transcription factor insulin promoter factor 1 (IPF1) to chromosome band 13q12.1 [15].
  • CONCLUSION: The common alleles of regulatory variants in the 5' enhancer and promoter regions of the IPF1 gene increase susceptibility to type 2 diabetes among African American individuals, likely as a result of gene-gene or gene-environment interactions [16].
  • Analysis of the regulatory region of the human LRH-1 gene demonstrated the presence of three functional binding sites for PDX-1 [17].
 

Anatomical context of PDX1

  • Adult rat liver cells transdifferentiated with lentiviral IPF1 vectors reverse diabetes in mice: an ex vivo gene therapy approach [3].
  • Here, we describe two novel mutations in the IPF1 gene leading to pancreas agenesis [14].
  • The human forkhead box O1A (FOXO1A) gene on chromosome 13q14.1 is a key transcription factor in insulin signaling in liver and adipose tissue and plays a central role in the regulation of key pancreatic beta-cell genes including IPF1 [18].
  • Since PDX-1 is highly enriched in beta and delta cells, these results suggest that this factor plays a principal role in defining islet beta cell- and delta cell-specific expression of the IAPP gene [19].
  • The GLUT2TAAT motif mediates the activation of the heterologous promoter in the PDX-1-expressing cell line but not in InR1-G9 or JEG-3 cell lines [20].
 

Associations of PDX1 with chemical compounds

  • We screened 40 Italian early-onset type 2 diabetic probands for IPF1 mutations, performed oral glucose tolerance tests in the unaffected family members, and performed in vitro functional studies of the mutant variant [2].
  • The control sequences conserved between mammalian insulin genes are acted upon by transcription factors, like PDX-1 and BETA-2, that are also involved in islet beta cell function and formation [21].
  • Role of a Proline Insertion in the Insulin Promoter Factor 1 (IPF1) Gene in African Americans With Type 2 Diabetes [22].
  • Treatment of MIN6 cells with an 18-mer phosphorothioate ODN complementary to a sequence starting at the translation initiation codon of PDX-1 caused a potent, concentration-dependent reduction in PDX-1 expression; addition of 2 microM antisense ODN could reduce PDX-1 expression to 14+/-4% of the control [23].
  • The major findings are that the A-box sites that bind PDX-1 are among the most highly conserved regulatory sequences, and that the conservation of the C1, E1, and CRE sequences emphasize the importance of MafA, E47/beta2, and cAMP-associated regulation [24].
 

Physical interactions of PDX1

  • This complex was displaced with an antiserum to IUF-1, confirming that IUF-1 binds to the human IAPP promoter in vitro [25].
  • EMSA results indicated that EX-4 caused a 12-fold increase in HNF3beta binding to PDX-1 promoter area II [26].
  • EMSAs demonstrated that PDX-1 can interact with the lactase promoter binding site but not with a site in which the core PDX-1 binding sequence TAAT is mutated [27].
  • The glucose-stimulated activation of IUF1 DNA binding and MAPKAP kinase-2 (but not the arsenite-induced activation of these proteins) was prevented by wortmannin and LY 294002 at concentrations similar to those that inhibit phosphatidylinositide 3-kinase [28].
  • Here we show that specific members of both PBX and MEIS subclasses form a multimeric complex with the pancreatic homeodomain protein PDX1 and switch the nature of its transcriptional activity [29].
 

Regulatory relationships of PDX1

  • We, therefore, investigated the potential role of PDX-1 in the transcriptional control of GLUT2 [20].
  • GLP-1 has been shown to be involved in stimulating the signaling pathways downstream of the transcription factor PDX-1, by increasing its protein and messenger RNA levels [30].
  • Multiple copies of the GLUT2TAAT motif were ligated 5' to a heterologous promoter and transfected into a PDX-1-expressing cell line (beta TC3) and into cell lines lacking the homeobox factor (InR1-G9 and JEG-3) [20].
  • This study aimed to determine the role of PDX-1 in regulating lactase gene promoter activity in intestinal epithelial cells [27].
  • SAPK2 then activates IUF1 indirectly by activating a novel IUF1-activating enzyme [28].
 

Other interactions of PDX1

  • These data demonstrate that the murine GLUT2 promoter is controlled by the PDX-1 homeobox factor through the identified GLUT2TAAT motif [20].
  • We concluded that GLP-1 induced differentiation of nestin-positive progenitor embryonic stem cells into insulin-producing cells, which was achieved by upregulation of PDX-1 expression [30].
  • Analysis of gene expression by RT-PCR showed the presence of islet developmental transcription factors neuroD, Nkx6.1, and PDX-1, as well as mature islet hormones [31].
  • Exendin-4 differentiation of a human pancreatic duct cell line into endocrine cells: involvement of PDX-1 and HNF3beta transcription factors [26].
  • Given the contrasting spatial expression pattern, PDX-1 may function to specify the anterior boundary of lactase expression in the small intestine and is thus a candidate regulator of anterior spatial restriction in the gut [27].
 

Analytical, diagnostic and therapeutic context of PDX1

References

  1. Genetic variation in the hepatocyte nuclear factor-3beta gene (HNF3B) does not contribute to maturity-onset diabetes of the young in French Caucasians. Abderrahmani, A., Chèvre, J.C., Otabe, S., Chikri, M., Hani, E.H., Vaxillaire, M., Hinokio, Y., Horikawa, Y., Bell, G.I., Froguel, P. Diabetes (2000) [Pubmed]
  2. IPF-1/MODY4 gene missense mutation in an Italian family with type 2 and gestational diabetes. Gragnoli, C., Stanojevic, V., Gorini, A., Von Preussenthal, G.M., Thomas, M.K., Habener, J.F. Metab. Clin. Exp. (2005) [Pubmed]
  3. Adult rat liver cells transdifferentiated with lentiviral IPF1 vectors reverse diabetes in mice: an ex vivo gene therapy approach. Fodor, A., Harel, C., Fodor, L., Armoni, M., Salmon, P., Trono, D., Karnieli, E. Diabetologia (2007) [Pubmed]
  4. Pancreas duodenum homeobox-1 regulates pancreas development during embryogenesis and islet cell function in adulthood. Hui, H., Perfetti, R. Eur. J. Endocrinol. (2002) [Pubmed]
  5. Transcription factors contributing to the pancreatic beta-cell phenotype. Madsen, O.D., Jensen, J., Petersen, H.V., Pedersen, E.E., Oster, A., Andersen, F.G., Jørgensen, M.C., Jensen, P.B., Larsson, L.I., Serup, P. Horm. Metab. Res. (1997) [Pubmed]
  6. Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Stoffers, D.A., Zinkin, N.T., Stanojevic, V., Clarke, W.L., Habener, J.F. Nat. Genet. (1997) [Pubmed]
  7. Early-onset type-II diabetes mellitus (MODY4) linked to IPF1. Stoffers, D.A., Ferrer, J., Clarke, W.L., Habener, J.F. Nat. Genet. (1997) [Pubmed]
  8. Missense mutations in the insulin promoter factor-1 gene predispose to type 2 diabetes. Macfarlane, W.M., Frayling, T.M., Ellard, S., Evans, J.C., Allen, L.I., Bulman, M.P., Ayres, S., Shepherd, M., Clark, P., Millward, A., Demaine, A., Wilkin, T., Docherty, K., Hattersley, A.T. J. Clin. Invest. (1999) [Pubmed]
  9. Defective mutations in the insulin promoter factor-1 (IPF-1) gene in late-onset type 2 diabetes mellitus. Hani, E.H., Stoffers, D.A., Chèvre, J.C., Durand, E., Stanojevic, V., Dina, C., Habener, J.F., Froguel, P. J. Clin. Invest. (1999) [Pubmed]
  10. Oxidative stress-mediated, post-translational loss of MafA protein as a contributing mechanism to loss of insulin gene expression in glucotoxic beta cells. Harmon, J.S., Stein, R., Robertson, R.P. J. Biol. Chem. (2005) [Pubmed]
  11. Mutations in the genes for hepatocyte nuclear factor (HNF)-1alpha, -4alpha, -1beta, and -3beta; the dimerization cofactor of HNF-1; and insulin promoter factor 1 are not common causes of early-onset type 2 diabetes in Pima Indians. Baier, L.J., Permana, P.A., Traurig, M., Dobberfuhl, A., Wiedrich, C., Sutherland, J., Thuillez, P., Luczy-Bachman, G., Hara, M., Horikawa, Y., Hinokio, Y., Hanson, R.L., Bogardus, C. Diabetes Care (2000) [Pubmed]
  12. Can we create new organs from our own tissues? Ferber, S. Isr. Med. Assoc. J. (2000) [Pubmed]
  13. Insulin promoter factor-1 mutations and diabetes in Trinidad: identification of a novel diabetes-associated mutation (E224K) in an Indo-Trinidadian family. Cockburn, B.N., Bermano, G., Boodram, L.L., Teelucksingh, S., Tsuchiya, T., Mahabir, D., Allan, A.B., Stein, R., Docherty, K., Bell, G.I. J. Clin. Endocrinol. Metab. (2004) [Pubmed]
  14. Agenesis of human pancreas due to decreased half-life of insulin promoter factor 1. Schwitzgebel, V.M., Mamin, A., Brun, T., Ritz-Laser, B., Zaiko, M., Maret, A., Jornayvaz, F.R., Theintz, G.E., Michielin, O., Melloul, D., Philippe, J. J. Clin. Endocrinol. Metab. (2003) [Pubmed]
  15. Localization of human homeodomain transcription factor insulin promoter factor 1 (IPF1) to chromosome band 13q12.1. Stoffel, M., Stein, R., Wright, C.V., Espinosa, R., Le Beau, M.M., Bell, G.I. Genomics (1995) [Pubmed]
  16. Insulin Promoter Factor 1 variation is associated with type 2 diabetes in African Americans. Karim, M.A., Wang, X., Hale, T.C., Elbein, S.C. BMC Med. Genet. (2005) [Pubmed]
  17. Pancreatic-duodenal homeobox 1 regulates expression of liver receptor homolog 1 during pancreas development. Annicotte, J.S., Fayard, E., Swift, G.H., Selander, L., Edlund, H., Tanaka, T., Kodama, T., Schoonjans, K., Auwerx, J. Mol. Cell. Biol. (2003) [Pubmed]
  18. Analysis of FOXO1A as a candidate gene for type 2 diabetes. Karim, M.A., Craig, R.L., Wang, X., Hale, T.C., Elbein, S.C. Mol. Genet. Metab. (2006) [Pubmed]
  19. Identification of cis- and trans-active factors regulating human islet amyloid polypeptide gene expression in pancreatic beta-cells. Carty, M.D., Lillquist, J.S., Peshavaria, M., Stein, R., Soeller, W.C. J. Biol. Chem. (1997) [Pubmed]
  20. Transcriptional activation of the GLUT2 gene by the IPF-1/STF-1/IDX-1 homeobox factor. Waeber, G., Thompson, N., Nicod, P., Bonny, C. Mol. Endocrinol. (1996) [Pubmed]
  21. Identification of a novel PDX-1 binding site in the human insulin gene enhancer. Le Lay, J., Matsuoka, T.A., Henderson, E., Stein, R. J. Biol. Chem. (2004) [Pubmed]
  22. Role of a Proline Insertion in the Insulin Promoter Factor 1 (IPF1) Gene in African Americans With Type 2 Diabetes. Elbein, S.C., Wang, X., Karim, M.A., Freedman, B.I., Bowden, D.W., Shuldiner, A.R., Brancati, F.L., Kao, W.H. Diabetes (2006) [Pubmed]
  23. Suppression of transcription factor PDX-1/IPF1/STF-1/IDX-1 causes no decrease in insulin mRNA in MIN6 cells. Kajimoto, Y., Watada, H., Matsuoka, T., Kaneto, H., Fujitani, Y., Miyazaki, J., Yamasaki, Y. J. Clin. Invest. (1997) [Pubmed]
  24. Comparative analysis of insulin gene promoters: implications for diabetes research. Hay, C.W., Docherty, K. Diabetes (2006) [Pubmed]
  25. Insulin upstream factor 1 and a novel ubiquitous factor bind to the human islet amyloid polypeptide/amylin gene promoter. Bretherton-Watt, D., Gore, N., Boam, D.S. Biochem. J. (1996) [Pubmed]
  26. Exendin-4 differentiation of a human pancreatic duct cell line into endocrine cells: involvement of PDX-1 and HNF3beta transcription factors. Zhou, J., Pineyro, M.A., Wang, X., Doyle, M.E., Egan, J.M. J. Cell. Physiol. (2002) [Pubmed]
  27. Transcriptional regulation of the lactase-phlorizin hydrolase promoter by PDX-1. Wang, Z., Fang, R., Olds, L.C., Sibley, E. Am. J. Physiol. Gastrointest. Liver Physiol. (2004) [Pubmed]
  28. 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. Macfarlane, W.M., Smith, S.B., James, R.F., Clifton, A.D., Doza, Y.N., Cohen, P., Docherty, K. J. Biol. Chem. (1997) [Pubmed]
  29. An endocrine-exocrine switch in the activity of the pancreatic homeodomain protein PDX1 through formation of a trimeric complex with PBX1b and MRG1 (MEIS2). Swift, G.H., Liu, Y., Rose, S.D., Bischof, L.J., Steelman, S., Buchberg, A.M., Wright, C.V., MacDonald, R.J. Mol. Cell. Biol. (1998) [Pubmed]
  30. Glucagon-like peptide-1 differentiation of primate embryonic stem cells into insulin-producing cells. Yue, F., Cui, L., Johkura, K., Ogiwara, N., Sasaki, K. Tissue Eng. (2006) [Pubmed]
  31. Enriched human pancreatic ductal cultures obtained from selective death of acinar cells express pancreatic and duodenal homeobox gene-1 age-dependently. Street, C.N., Lakey, J.R., Rajotte, R.V., Shapiro, A.M., Kieffer, T.J., Lyon, J.G., Kin, T., Korbutt, G.S. The review of diabetic studies : RDS (2004) [Pubmed]
  32. The pancreatic homeodomain transcription factor IDX1/IPF1 is expressed in neural cells during brain development. Perez-Villamil, B., Schwartz, P.T., Vallejo, M. Endocrinology (1999) [Pubmed]
  33. Adult human cytokeratin 19-positive cells reexpress insulin promoter factor 1 in vitro: further evidence for pluripotent pancreatic stem cells in humans. Gmyr, V., Kerr-Conte, J., Belaich, S., Vandewalle, B., Leteurtre, E., Vantyghem, M.C., Lecomte-Houcke, M., Proye, C., Lefebvre, J., Pattou, F. Diabetes (2000) [Pubmed]
 
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