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PDX1 (pancreatic and duodenal homeobox 1)

Identity

Other namesGSF
IDX-1
IPF1
IUF1
MODY4
PDX-1
STF-1
HGNC (Hugo) PDX1
LocusID (NCBI) 3651
Location 13q12.2
Location_base_pair Starts at 28494168 and ends at 28500451 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

Description PDX-1 gene is located at human chromosome 13q12.1, mouse chromosome 5qG3 and rat chromosome 12, respectively.
PDX-1 gene consists of two exons spanning a region of about 6 kb. In the promoter region of PDX-1, there are three highly conserved regions, termed "Area I-II-III" which are located between -2800 and -1600 base pairs (bp), and a forth distal enhancer element, termed "Area IV" which is located between -6500 and -6045 bp. These enhancer elements harbor binding sites for multiple transcription factors and transcriptional regulators such as HNF-1alpha, HNF-3beta, HNF-6, Foxa1, Foxa2, Pax6, MafA and PDX-1 itself. Areas I and II impart endocrine expression, while Area III confers beta-cell specificity. Area IV is capable of independently directing pancreatic beta-cell-specific reporter gene expression and potentiating the proximal enhancer activity.
Transcription PDX-1 mRNA has an open reading frame of 849 bp.

Protein

 
  Figure 1. Schematic representation of functional domains and phosphorylation sites of PDX-1. The numbers indicate the positions of phosphorylation sites and functional domains on the polypeptide chain of human PDX-1. NLS: Nuclear localization signal; PTD: Protein transduction domain; S: Serine; T: Threonine.
Description Human PDX-1 is a protein of 283 amino acids with a calculated molecular weight of 30.64 kDa. However, endogenous PDX-1 is usually detected as a protein with molecular mass of 46 kDa, likely due to posttranslational modifications such as phosphorylation and sumoylation. The N-terminus of PDX-1 contains a transactivation domain. The middle region contains a homeodomain, which is essential for DNA binding and protein-protein interactions. Within the homeodomain, there is an antennapedia-like protein transduction domain (PTD) which allows PDX-1 to permeate into cells and a nuclear localization signal (NLS) motif, RRMKWKK(197-203aa), which is sufficient for the nuclear import of PDX-1. There is a conserved motif in the C-terminus of PDX-1 that mediates the PDX-1-PCIF1 interaction resulting in the inhibition of PDX-1 transcriptional activity. Several C-terminal residues such as Gly 212, Glu 224 and Pro 239 are essential for full transactivation of PDX-1 as evidenced by the association of their missense mutations with diabetes (Fig. 2). Several potential phosphorylation sites within PDX-1 have been identified, such as Thr 11 by DNA-PK, Ser 61 and 66 by GSK3beta, Thr 152 by PASK, Thr 231 and Ser 232 by CK2 and Ser 268 by AKT-GSK and HIPK2.
Expression PDX-1 is expressed as early as embryonic day 8.5 (E8.5) in the dorsal and ventral endoderm regions that give rise to pancreatic buds, as well as in the common bile duct, distal stomach, Brunner's glands, and duodenal epithelium. During pancreas development, PDX-1 is expressed in all pancreatic precursor cells. PDX-1 expression becomes restricted to beta cells and a small subpopulation of delta and PP cells in adult. Low levels of PDX-1 are also detected in the nuclei of acinar cells. PDX-1 is also expressed in the gastric antrum and duodenum in adult.
The compartmentalization of PDX-1 is lost under pathological conditions. Aberrant overexpression of PDX-1 is observed in a number of human cancers such as pancreatic, gastric, colon, breast, prostate, colorectal, kidney cancer and paediatric solid pseudopapillary tumors. Up-regulated PDX-1 expression is also observed in premalignant metaplastic ductal epithelium during transforming growth factor (TGF)-alpha-induced pancreatic ductal metaplasia and neoplasia.
PDX-1 expression is subject to regulation by glucose, glucagon-like peptide 1 (GLP-1), palmitic acid, peroxisome proliferator-activated receptor-alpha (PPARalpha) and PPARgamma, epidermal growth factor (EGF) and high fat diet.
Localisation PDX-1 is localized in the Nucleus of the cells. In solid pseudopapillary tumors (SPT), however, PDX-1 only exists in the cytoplasm, but not in the nucleus.
Function Pancreatic and duodenal homeobox-1 (PDX-1) is a homeodomain-containing transcription factor essential for pancreatic development, beta-cell differentiation and the maintenance of mature beta cell function through regulating the expression of key endocrine beta-cell-specific genes such as insulin, glucokinase, islet amyloid polypeptide and the glucose transporter type 2. PDX-1 also regulates the expression of elastase I in pancreatic ductal and acinar cells. PDX-1 is functionally involved in mitochondrial signal generation in the moment-to-moment control of insulin release by regulating mitochondrial transcription factor A (TFAM).
Homology Human PDX-1 shares a 90% amino acid homology with hamster, 88% with rat, 87% with mouse and 68% with Xenopus. Zebrafish PDX-1 shares a 95% amino acid identity to mammalian PDX-1 in the homeodomain.

Mutations

 
  Figure 2. Diabetes-associated genetic mutations of PDX-1. MODY4/3: maturity-onset diabetes of young 43; P: proline; C: cysteine; E: glutamic acid; K: lysine; R: arginine; Q: glutamine; L: leucine; D: aspartic acid; N: asparagine; G: glycine; H: histidine.
Somatic Pro63fsdelC: a frameshift mutation resulting from a single nucleotide deletion within codon 63 in exon 1 of the coding sequence of PDX-1. The point deletion causes a frame shift resulting in the translation of 59 novel codons before termination and the production of a prematurely terminated truncated protein of 16 kDa.
InsCCG243: an in-frame proline insertion mutation at codon 243 of PDX-1.
Missense mutations: C18R, P33T, Q59L, D76N, E178G, R197H, G212R, E224K and P239Q. These missense mutants show either a decreased binding activity to the insulin gene promoter (C18R, P33T, D76N and R197H) or a reduced transactivity (C18R, P33T, Q59L, D76N, E178G, R197H, G212R, E224K and P239Q) compared to wild-type PDX-1.

Implicated in

Entity Various cancers
Prognosis Elevated expression of PDX-1 is found in a number of human cancers, including pancreatic, breast, prostate cancer, colorectal cancer, colon cancer, kidney, gastric, paediatric solid pseudopapillary tumors (SPT) and intestinal-type ovarian mucinous neoplasm (OMN). Elevated expression level of PDX-1 in pancreatic cancer is significantly correlated with lymph node metastasis, TNM grading, pathological grading and tumor cell proliferation. PDX-1 expression in pancreatic cancer is an independent survival factor since the patients with positive PDX-1 have a significantly worse prognosis than those patients with negative PDX-1. In colorectal cancer, PDX-1 is highly expressed in hepatic metastasis of colorectal cancer, while lower expression of PDX-1 is found in primary colorectal tumor. Metastatic colorectal adenocarcinoma in the ovarian is also positive for PDX-1. PDX-1 expression also correlates with histological type and depth of invasion of gastric carcinomas.
  
Entity Diabetes
Prognosis Maturity-onset diabetes of young 4 (MODY4) is a form of early-onset type-II diabetes mellitus in which expression of diabetes occurs later than that observed for MODY1, MODY2 and MODY3. Pro63fsdelC of PDX-1 contributes to the development of MODY4 when the mutation is heterozygous. InsCCG243, PDX-1 P33T and PDX-1 E224K mutations also contribute to the development of MODY4. Two missense mutations (D76N and P239Q) in PDX-1 are found in MODY3 families. Five missense mutations (C18R, Q59L, D76N, E178G and R197H) in PDX-1 are found in patients with Non-MODY type 2 diabetes.
  

External links

Nomenclature
HGNC (Hugo)PDX1   6107
Cards
AtlasPDX1ID43921ch13q12
Entrez_Gene (NCBI)PDX1  3651  pancreatic and duodenal homeobox 1
GeneCards (Weizmann)PDX1
Ensembl (Hinxton)ENSG00000139515 [Gene_View]  chr13:28494168-28500451 [Contig_View]  PDX1 [Vega]
ICGC DataPortalENSG00000139515
cBioPortalPDX1
AceView (NCBI)PDX1
Genatlas (Paris)PDX1
WikiGenes3651
SOURCE (Princeton)NM_000209
Genomic and cartography
GoldenPath (UCSC)PDX1  -  13q12.2   chr13:28494168-28500451 +  13q12.1   [Description]    (hg19-Feb_2009)
EnsemblPDX1 - 13q12.1 [CytoView]
Mapping of homologs : NCBIPDX1 [Mapview]
OMIM125853   260370   600733   606176   606392   
Gene and transcription
Genbank (Entrez)AF049893 BC111592 CA771381 CA848737 U30329
RefSeq transcript (Entrez)NM_000209
RefSeq genomic (Entrez)AC_000145 NC_000013 NC_018924 NG_008183 NT_024524 NW_001838071 NW_004929388
Consensus coding sequences : CCDS (NCBI)PDX1
Cluster EST : UnigeneHs.32938 [ NCBI ]
CGAP (NCI)Hs.32938
Alternative Splicing : Fast-db (Paris)GSHG0008013
Alternative Splicing GalleryENSG00000139515
Gene ExpressionPDX1 [ NCBI-GEO ]     PDX1 [ SEEK ]   PDX1 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP52945 (Uniprot)
NextProtP52945  [Medical]
With graphics : InterProP52945
Splice isoforms : SwissVarP52945 (Swissvar)
Domaine pattern : Prosite (Expaxy)HOMEOBOX_1 (PS00027)    HOMEOBOX_2 (PS50071)   
Domains : Interpro (EBI)Homeobox_antennapedia [organisation]   Homeobox_CS [organisation]   Homeobox_dom [organisation]   Homeobox_metazoa [organisation]   Homeodomain-like [organisation]  
Related proteins : CluSTrP52945
Domain families : Pfam (Sanger)Homeobox (PF00046)   
Domain families : Pfam (NCBI)pfam00046   
Domain families : Smart (EMBL)HOX (SM00389)  
DMDM Disease mutations3651
Blocks (Seattle)P52945
Human Protein AtlasENSG00000139515 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasP52945
HPRD02843
IPIIPI00006036   
Protein Interaction databases
DIP (DOE-UCLA)P52945
IntAct (EBI)P52945
FunCoupENSG00000139515
BioGRIDPDX1
InParanoidP52945
Interologous Interaction database P52945
IntegromeDBPDX1
STRING (EMBL)PDX1
Ontologies - Pathways
Ontology : AmiGOnegative regulation of transcription from RNA polymerase II promoter  core promoter sequence-specific DNA binding  liver development  type B pancreatic cell differentiation  type B pancreatic cell differentiation  chromatin binding  sequence-specific DNA binding transcription factor activity  nucleus  cytosol  glucose metabolic process  generation of precursor metabolites and energy  transcription from RNA polymerase II promoter  smoothened signaling pathway  nitric oxide mediated signal transduction  central nervous system development  transcription factor binding  positive regulation of cell proliferation  negative regulation of cell proliferation  response to wounding  organ morphogenesis  response to iron(II) ion  response to chlorate  organ senescence  positive regulation of cell death  morphogenesis of embryonic epithelium  insulin secretion  exocrine pancreas development  endocrine pancreas development  organ regeneration  positive regulation of insulin secretion  protein complex binding  response to vitamin  response to cytokine  response to nicotine  response to drug  glucose homeostasis  response to leucine  positive regulation of DNA binding  positive regulation of transcription from RNA polymerase II promoter  protein heterodimerization activity  digestive tract development  stem cell differentiation  response to glucocorticoid  detection of glucose  transdifferentiation  response to fatty acid  
Ontology : EGO-EBInegative regulation of transcription from RNA polymerase II promoter  core promoter sequence-specific DNA binding  liver development  type B pancreatic cell differentiation  type B pancreatic cell differentiation  chromatin binding  sequence-specific DNA binding transcription factor activity  nucleus  cytosol  glucose metabolic process  generation of precursor metabolites and energy  transcription from RNA polymerase II promoter  smoothened signaling pathway  nitric oxide mediated signal transduction  central nervous system development  transcription factor binding  positive regulation of cell proliferation  negative regulation of cell proliferation  response to wounding  organ morphogenesis  response to iron(II) ion  response to chlorate  organ senescence  positive regulation of cell death  morphogenesis of embryonic epithelium  insulin secretion  exocrine pancreas development  endocrine pancreas development  organ regeneration  positive regulation of insulin secretion  protein complex binding  response to vitamin  response to cytokine  response to nicotine  response to drug  glucose homeostasis  response to leucine  positive regulation of DNA binding  positive regulation of transcription from RNA polymerase II promoter  protein heterodimerization activity  digestive tract development  stem cell differentiation  response to glucocorticoid  detection of glucose  transdifferentiation  response to fatty acid  
Pathways : KEGGInsulin secretion    Type II diabetes mellitus    Maturity onset diabetes of the young   
Protein Interaction DatabasePDX1
Wikipedia pathwaysPDX1
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)PDX1
snp3D : Map Gene to Disease3651
SNP (GeneSNP Utah)PDX1
SNP : HGBasePDX1
Genetic variants : HAPMAPPDX1
Exome VariantPDX1
1000_GenomesPDX1 
ICGC programENSG00000139515 
Somatic Mutations in Cancer : COSMICPDX1 
CONAN: Copy Number AnalysisPDX1 
Mutations and Diseases : HGMDPDX1
Genomic VariantsPDX1  PDX1 [DGVbeta]
dbVarPDX1
ClinVarPDX1
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM125853    260370    600733    606176    606392   
MedgenPDX1
GENETestsPDX1
Disease Genetic AssociationPDX1
Huge Navigator PDX1 [HugePedia]  PDX1 [HugeCancerGEM]
General knowledge
Homologs : HomoloGenePDX1
Homology/Alignments : Family Browser (UCSC)PDX1
Phylogenetic Trees/Animal Genes : TreeFamPDX1
Chemical/Protein Interactions : CTD3651
Chemical/Pharm GKB GenePA162399173
Clinical trialPDX1
Cancer Resource (Charite)ENSG00000139515
Other databases
Probes
Litterature
PubMed137 Pubmed reference(s) in Entrez
CoreMinePDX1
iHOPPDX1
OncoSearchPDX1

Bibliography

Early-onset type-II diabetes mellitus (MODY4) linked to IPF1.
Stoffers DA, Ferrer J, Clarke WL, Habener JF.
Nat Genet. 1997 Oct;17(2):138-9.
PMID 9326926
 
Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence.
Stoffers DA, Zinkin NT, Stanojevic V, Clarke WL, Habener JF.
Nat Genet. 1997 Jan;15(1):106-10.
PMID 8988180
 
Insulin promoter factor-1 gene mutation linked to early-onset type 2 diabetes mellitus directs expression of a dominant negative isoprotein.
Stoffers DA, Stanojevic V, Habener JF.
J Clin Invest. 1998 Jul 1;102(1):232-41.
PMID 9649577
 
Defective mutations in the insulin promoter factor-1 (IPF-1) gene in late-onset type 2 diabetes mellitus.
Hani EH, Stoffers DA, Chevre JC, Durand E, Stanojevic V, Dina C, Habener JF, Froguel P.
J Clin Invest. 1999 Nov;104(9):R41-8.
PMID 10545531
 
Identification of a nuclear localization signal, RRMKWKK, in the homeodomain transcription factor PDX-1.
Moede T, Leibiger B, Pour HG, Berggren P, Leibiger IB.
FEBS Lett. 1999 Nov 19;461(3):229-34.
PMID 10567702
 
Missense mutations in the insulin promoter factor-1 gene predispose to type 2 diabetes
Macfarlane WM, Frayling TM, Ellard S, Evans JC, Allen LI, Bulman MP, Ayers S, Shepherd M, Clark P, Millward A, Demaine A, Wilken T, Docherty K, Hattersley AT.
J Clin Invest. 2000 Sep;106(5):717.
PMID 10974025
 
Functional consequences of mutations in the MODY4 gene (IPF1) and coexistence with MODY3 mutations.
Weng J, Macfarlane WM, Lehto M, Gu HF, Shepherd LM, Ivarsson SA, Wibell L, Smith T, Groop LC.
Diabetologia. 2001 Feb;44(2):249-58.
PMID 11270685
 
PDX-1 protein containing its own antennapedia-like protein transduction domain can transduce pancreatic duct and islet cells.
Noguchi H, Kaneto H, Weir GC, Bonner-Weir S.
Diabetes. 2003 Jul;52(7):1732-7.
PMID 12829640
 
PDX-1 and the pancreas.
Ashizawa S, Brunicardi FC, Wang XP.
Pancreas. 2004 Mar;28(2):109-20. (REVIEW)
PMID 15028942
 
Insulin promoter factor-1 mutations and diabetes in Trinidad: identification of a novel diabetes-associated mutation (E224K) in an Indo-Trinidadian family.
Cockburn BN, Bermano G, Boodram LL, Teelucksingh S, Tsuchiya T, Mahabir D, Allan AB, Stein R, Docherty K, Bell GI.
J Clin Endocrinol Metab. 2004 Feb;89(2):971-8.
PMID 14764823
 
PDX1 homeobox protein expression in pseudopyloric glands and gastric carcinomas.
Sakai H, Eishi Y, Li XL, Akiyama Y, Miyake S, Takizawa T, Konishi N, Tatematsu M, Koike M, Yuasa Y.
Gut. 2004 Mar;53(3):323-30.
PMID 14960508
 
IPF-1/MODY4 gene missense mutation in an Italian family with type 2 and gestational diabetes.
Gragnoli C, Stanojevic V, Gorini A, Von Preussenthal GM, Thomas MK, Habener JF.
Metabolism. 2005 Aug;54(8):983-8.
PMID 16092045
 
Tissue MicroArray analyses of pancreatic duodenal homeobox-1 in human cancers.
Wang XP, Li ZJ, Magnusson J, Brunicardi FC.
World J Surg. 2005 Mar;29(3):334-8.
PMID 15706433
 
Expression of Pdx-1 in human gastric metaplasia and gastric adenocarcinoma.
Leys CM, Nomura S, Rudzinski E, Kaminishi M, Montgomery E, Washington MK, Goldenring JR.
Hum Pathol. 2006 Sep;37(9):1162-8. Epub 2006 Jul 7.
PMID 16938521
 
Crucial role of PDX-1 in pancreas development, beta-cell differentiation, and induction of surrogate beta-cells.
Kaneto H, Miyatsuka T, Shiraiwa T, Yamamoto K, Kato K, Fujitani Y, Matsuoka TA.
Curr Med Chem. 2007;14(16):1745-52. (REVIEW)
PMID 17627512
 
Pancreatic duodenal homeobox factor-1 and diabetes mellitus type 2 (review).
Al-Quobaili F, Montenarh M.
Int J Mol Med. 2008 Apr;21(4):399-404. (REVIEW)
PMID 18360684
 
Transcription factor PDX-1 in human colorectal adenocarcinoma: a potential tumor marker?
Ballian N, Liu SH, Brunicardi FC.
World J Gastroenterol. 2008 Oct 14;14(38):5823-6.
PMID 18855980
 
Transcription factors involved in pancreas development are expressed in paediatric solid pseudopapillary tumours.
Galmiche L, Sarnacki S, Verkarre V, Boizet B, Duvillie B, Fabre M, Jaubert F.
Histopathology. 2008 Sep;53(3):318-24. Epub 2008 Jul 29.
PMID 18671802
 
Expression of PDX-1 in prostate cancer, prostatic intraepithelial neoplasia and benign prostatic tissue.
Jonmarker S, Glaessgen A, Culp WD, Pisa P, Lewensohn R, Ekman P, Valdman A, Egevad L.
APMIS. 2008 Jun;116(6):491-8.
PMID 18754323
 
Intestinal type and endocervical-like ovarian mucinous neoplasms are immunophenotypically distinct entities.
Lin X, Lindner JL, Silverman JF, Liu Y.
Appl Immunohistochem Mol Morphol. 2008 Oct;16(5):453-8.
PMID 18665037
 
Pancreatic duodenal homeobox-1 (PDX1) functions as a tumor suppressor in gastric cancer.
Ma J, Chen M, Wang J, Xia HH, Zhu S, Liang Y, Gu Q, Qiao L, Dai Y, Zou B, Li Z, Zhang Y, Lan H, Wong BC.
Carcinogenesis. 2008 Jul;29(7):1327-33. Epub 2008 May 13.
PMID 18477649
 
PDX1 deficiency causes mitochondrial dysfunction and defective insulin secretion through TFAM suppression.
Gauthier BR, Wiederkehr A, Baquie M, Dai C, Powers AC, Kerr-Conte J, Pattou F, MacDonald RJ, Ferrer J, Wollheim CB.
Cell Metab. 2009 Aug;10(2):110-8.
PMID 19656489
 
The expression pattern of PDX-1, SHH, Patched and Gli-1 is associated with pathological and clinical features in human pancreatic cancer.
Quint K, Stintzing S, Alinger B, Hauser-Kronberger C, Dietze O, Gahr S, Hahn EG, Ocker M, Neureiter D.
Pancreatology. 2009;9(1-2):116-26. Epub 2008 Dec 13.
PMID 19077462
 
Pancreatic and duodenal homeobox 1 (PDX1) phosphorylation at serine-269 is HIPK2-dependent and affects PDX1 subnuclear localization.
An R, da Silva Xavier G, Semplici F, Vakhshouri S, Hao HX, Rutter J, Pagano MA, Meggio F, Pinna LA, Rutter GA.
Biochem Biophys Res Commun. 2010 Aug 20;399(2):155-61. Epub 2010 Jul 15.
PMID 20637728
 
Glucose regulates steady-state levels of PDX1 via the reciprocal actions of GSK3 and AKT kinases.
Humphrey RK, Yu SM, Flores LE, Jhala US.
J Biol Chem. 2010 Jan 29;285(5):3406-16. Epub 2009 Oct 15.
PMID 19833727
 
PDX-1: demonstration of oncogenic properties in pancreatic cancer.
Liu SH, Patel S, Gingras MC, Nemunaitis J, Zhou G, Chen C, Li M, Fisher W, Gibbs R, Brunicardi FC.
Cancer. 2010 Sep 30. [Epub ahead of print]
PMID 20886630
 
A novel hypomorphic PDX1 mutation responsible for permanent neonatal diabetes with subclinical exocrine deficiency.
Nicolino M, Claiborn KC, Senee V, Boland A, Stoffers DA, Julier C.
Diabetes. 2010 Mar;59(3):733-40. Epub 2009 Dec 15.
PMID 20009086
 
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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Contributor(s)

Written10-2010Guisheng Zhou, F Charles Brunicardi
Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas 77030, USA

Citation

This paper should be referenced as such :
Zhou, G ; Brunicardi, FC
PDX1 (pancreatic and duodenal homeobox 1)
Atlas Genet Cytogenet Oncol Haematol. 2011;15(6):-.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/PDX1ID43921ch13q12.html

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indexed on : Wed Jul 30 16:32:38 CEST 2014

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