PDX1 (pancreatic and duodenal homeobox 1)

2010-10-01   Guisheng Zhou , F Charles Brunicardi 

Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas 77030, USA

Identity

HGNC
LOCATION
13q12.2
LOCUSID
ALIAS
GSF,IDX-1,IPF1,IUF1,MODY4,PAGEN1,PDX-1,STF-1

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.

Proteins

Atlas Image
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, Brunners 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

Atlas Image
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 name
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 name
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.

Bibliography

Pubmed IDLast YearTitleAuthors
183606842008Pancreatic duodenal homeobox factor-1 and diabetes mellitus type 2 (review).Al-Quobaili F et al
206377282010Pancreatic and duodenal homeobox 1 (PDX1) phosphorylation at serine-269 is HIPK2-dependent and affects PDX1 subnuclear localization.An R et al
150289422004PDX-1 and the pancreas.Ashizawa S et al
188559802008Transcription factor PDX-1 in human colorectal adenocarcinoma: a potential tumor marker?Ballian N et al
147648232004Insulin promoter factor-1 mutations and diabetes in Trinidad: identification of a novel diabetes-associated mutation (E224K) in an Indo-Trinidadian family.Cockburn BN et al
186718022008Transcription factors involved in pancreas development are expressed in paediatric solid pseudopapillary tumours.Galmiche L et al
196564892009PDX1 deficiency causes mitochondrial dysfunction and defective insulin secretion through TFAM suppression.Gauthier BR et al
160920452005IPF-1/MODY4 gene missense mutation in an Italian family with type 2 and gestational diabetes.Gragnoli C et al
105455311999Defective mutations in the insulin promoter factor-1 (IPF-1) gene in late-onset type 2 diabetes mellitus.Hani EH et al
198337272010Glucose regulates steady-state levels of PDX1 via the reciprocal actions of GSK3 and AKT kinases.Humphrey RK et al
187543232008Expression of PDX-1 in prostate cancer, prostatic intraepithelial neoplasia and benign prostatic tissue.Jonmarker S et al
176275122007Crucial role of PDX-1 in pancreas development, beta-cell differentiation, and induction of surrogate beta-cells.Kaneto H et al
169385212006Expression of Pdx-1 in human gastric metaplasia and gastric adenocarcinoma.Leys CM et al
186650372008Intestinal type and endocervical-like ovarian mucinous neoplasms are immunophenotypically distinct entities.Lin X et al
208866302011PDX-1: demonstration of oncogenic properties in pancreatic cancer.Liu SH et al
184776492008Pancreatic duodenal homeobox-1 (PDX1) functions as a tumor suppressor in gastric cancer.Ma J et al
109740252000Missense mutations in the insulin promoter factor-1 gene predispose to type 2 diabetes.Macfarlane WM et al
105677021999Identification of a nuclear localization signal, RRMKWKK, in the homeodomain transcription factor PDX-1.Moede T et al
200090862010A novel hypomorphic PDX1 mutation responsible for permanent neonatal diabetes with subclinical exocrine deficiency.Nicolino M et al
128296402003PDX-1 protein containing its own antennapedia-like protein transduction domain can transduce pancreatic duct and islet cells.Noguchi H et al
190774622009The expression pattern of PDX-1, SHH, Patched and Gli-1 is associated with pathological and clinical features in human pancreatic cancer.Quint K et al
149605082004PDX1 homeobox protein expression in pseudopyloric glands and gastric carcinomas.Sakai H et al
96495771998Insulin promoter factor-1 gene mutation linked to early-onset type 2 diabetes mellitus directs expression of a dominant negative isoprotein.Stoffers DA et al
157064332005Tissue MicroArray analyses of pancreatic duodenal homeobox-1 in human cancers.Wang XP et al
112706852001Functional consequences of mutations in the MODY4 gene (IPF1) and coexistence with MODY3 mutations.Weng J et al

Other Information

Locus ID:

NCBI: 3651
MIM: 600733
HGNC: 6107
Ensembl: ENSG00000139515

Variants:

dbSNP: 3651
ClinVar: 3651
TCGA: ENSG00000139515
COSMIC: PDX1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000139515ENST00000381033P52945

Expression (GTEx)

0
1
2
3
4
5
6
7
8
9
10

Pathways

PathwaySourceExternal ID
Type II diabetes mellitusKEGGko04930
Maturity onset diabetes of the youngKEGGko04950
Type II diabetes mellitusKEGGhsa04930
Maturity onset diabetes of the youngKEGGhsa04950
Insulin secretionKEGGhsa04911
Developmental BiologyREACTOMER-HSA-1266738
Regulation of beta-cell developmentREACTOMER-HSA-186712
Regulation of gene expression in early pancreatic precursor cellsREACTOMER-HSA-210747
Regulation of gene expression in beta cellsREACTOMER-HSA-210745

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA24684AKT1GenePathwayassociated

References

Pubmed IDYearTitleCitations
238636252013Inactivation of specific β cell transcription factors in type 2 diabetes.162
244641002014Identification of low-frequency and rare sequence variants associated with elevated or reduced risk of type 2 diabetes.111
206826872010Common variants in 40 genes assessed for diabetes incidence and response to metformin and lifestyle intervention in the diabetes prevention program.88
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
225703312012Increased DNA methylation and decreased expression of PDX-1 in pancreatic islets from patients with type 2 diabetes.79
173274362007Evaluation of common variants in the six known maturity-onset diabetes of the young (MODY) genes for association with type 2 diabetes.74
164072092006Phosphorylation marks IPF1/PDX1 protein for degradation by glycogen synthase kinase 3-dependent mechanisms.48
150476182004Regulated expression of pdx-1 promotes in vitro differentiation of insulin-producing cells from embryonic stem cells.45
129703162003Agenesis of human pancreas due to decreased half-life of insulin promoter factor 1.44
161412092005Pdx-1 links histone H3-Lys-4 methylation to RNA polymerase II elongation during activation of insulin transcription.44

Citation

Guisheng Zhou ; F Charles Brunicardi

PDX1 (pancreatic and duodenal homeobox 1)

Atlas Genet Cytogenet Oncol Haematol. 2010-10-01

Online version: http://atlasgeneticsoncology.org/gene/43921/pdx1-(pancreatic-and-duodenal-homeobox-1)