You're using an outdated browser. Please upgrade to a modern browser for the best experience.
Submitted Successfully!
Thank you for your contribution! You can also upload a video entry or images related to this topic. For video creation, please contact our Academic Video Service.
Version Summary Created by Modification Content Size Created at Operation
1
Yanjiao Zhang
 -- 2807 2022-12-21 05:57:16 |
2 layout
Camila Xu
 Meta information modification 2807 2022-12-21 07:07:43 |

Video Upload Options

We provide professional Academic Video Service to translate complex research into visually appealing presentations. Would you like to try it?
No, upload directly Yes

Confirm

Are you sure to Delete?
Yes No
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Zhang, Y.;  Fang, X.;  Wei, J.;  Miao, R.;  Wu, H.;  Ma, K.;  Tian, J. PDX-1. Encyclopedia. Available online: https://encyclopedia.pub/entry/39012 (accessed on 15 July 2025).
Zhang Y,  Fang X,  Wei J,  Miao R,  Wu H,  Ma K, et al. PDX-1. Encyclopedia. Available at: https://encyclopedia.pub/entry/39012. Accessed July 15, 2025.
Zhang, Yanjiao, Xinyi Fang, Jiahua Wei, Runyu Miao, Haoran Wu, Kaile Ma, Jiaxing Tian. "PDX-1" Encyclopedia, https://encyclopedia.pub/entry/39012 (accessed July 15, 2025).
Zhang, Y.,  Fang, X.,  Wei, J.,  Miao, R.,  Wu, H.,  Ma, K., & Tian, J. (2022, December 21). PDX-1. In Encyclopedia. https://encyclopedia.pub/entry/39012
Zhang, Yanjiao, et al. "PDX-1." Encyclopedia. Web. 21 December, 2022.
PDX-1
Edit
This entry is adapted from the peer-reviewed paper 10.3390/biom12121785

The PDX-1, also known as IUF-1 (insulin upstream factor 1), IPF-1 (insulin promoter factor 1), STF-1 (somatostatin transcription factor 1), and IDX-1 (islet/duodenum homeobox-1), is a member of the homeodomain (HD)-containing transcription factor family and was first found in Xenopus laevis.

PDX-1 diabetes mellitus reversal transcription factor

1. Introduction

Diabetes mellitus (DM) is a metabolic disorder with an increasing prevalence worldwide. It is characterized by chronic hyperglycemia and disturbances in protein, carbohydrate, and fat metabolism due to insulin resistance (IR) and/or insulin secretion deficiency [1]. Approximately one billion people suffer from chronic hyperglycemia globally, a major public health problem. The International Diabetes Federation estimates that 10.5% (537 million) of adults aged 20–79 years are currently living with DM, and this prevalence is expected to increase to 11.3% (643 million) by 2030 and 12.2% (783 million) by 2045. With 1.541 million adults having impaired glucose tolerance (IGT), their risk for type 2 diabetes is increased [2]. Diabetes causes a series of complications, including blindness, renal failure, stroke, and coronary artery disease, resulting in a huge medical burden on society [3]. Furthermore, diabetes costs at least 966 billion dollars in health expenditure, a 316% increase over the last 15 years [2].
DM is divided into type 1 diabetes (insulin-dependent diabetes mellitus (T1DM or IDDM)), type 2 diabetes (non-insulin-dependent diabetes mellitus (T2DM or NIDDM)), specific types of diabetes due to other causes, and gestational diabetes mellitus [4][5]. T2DM is the most common presentation of DM, accounting for approximately 90% of DM cases, whereas T1DM constitutes more than 5% [6][7]. T2DM is a chronic multisystem disease characterized by insulin resistance and elevated blood glucose levels [8]. It is the result of a complex interplay between genetic, epigenetic, and environmental factors [9][10]. However, its etiology and pathogenesis have not yet been fully elucidated. The traditional view is that diabetes can only be controlled and not cured. Authoritative guidelines and clinical diabetes research mostly focus on controlling blood glucose levels and improving complications. Blood glucose levels are controlled by promoting insulin secretion, enhancing insulin sensitivity, and promoting glucose absorption by other tissues outside the islets of Langerhans [11][12]. With recent advances in diabetes research and medical technology progress, researchers have discovered new methods for preventing and treating diabetes with promising results. The terms “Diabetes reversal” and “Diabetes remission” have been used in scientific articles. They connote a glycosylated hemoglobin A1c (HbA1c) level of <6.5% (<48 mmol/mol) for at least 3 months without the usual glucose-lowering pharmacotherapy [13]. The reversal strategy, mechanism, and predictors are becoming increasingly clear with further research [14][15][16][17]. One of the possible mechanisms of diabetes reversal is that the removal of excess fat in the liver and pancreas can normalize hepatic glucose production and β-cell redifferentiation [14]. However, more studies are needed on the mechanism of diabetes reversal.
Studies on the role of PDX-1 in reversing diabetes are on the increase. PDX-1 regulates pancreatic development, β-cell differentiation, and the maintenance of mature β-cell function [18][19][20][21][22][23][24]. Non-β-cell can be reprogrammed by the transcription factors PDX-1 and musculoaponeurotic fibrosarcoma oncogene family A (MafA) into functional β-cell, which secretes insulin to restore blood glucose levels [25][26]. In contrast, β-cell-specific removal of PDX-1 resulted in pancreatic agenesis and severe hyperglycemia [27][28]. Thus, promoting PDX-1 expression can be an effective strategy to ameliorate β-cell dysfunction and diabetes progression, making PDX-1 a new target for developing anti-diabetic drugs.

2. Gene Structure and Location, Protein Molecular Structure, Distribution, and Expression of PDX-1

The PDX-1, also known as IUF-1 (insulin upstream factor 1), IPF-1 (insulin promoter factor 1), STF-1 (somatostatin transcription factor 1), and IDX-1 (islet/duodenum homeobox-1), is a member of the homeodomain (HD)-containing transcription factor family and was first found in Xenopus laevis [18][29][30][31][32]. It plays a key role in the genesis, development, and maturation of the pancreas and is also one of the factors necessary for maintaining normal pancreatic islet function.

2.1. Localization and Molecular Structure of PDX-1

Rat and mouse PDX-1 genes are localized on chromosomes 12 and 5, respectively, whereas the human PDX-1 gene is located on chromosome 13q12 (12.1) [33][34][35][36]. The human PDX-1 gene is approximately 6 Kb long with two exons. The first exon encodes the NH2-terminal region and some HD, while the second encodes the remaining HD and the COOH-terminal domain [37]. (Figure 1) Three nuclease-hypersensitive sites were identified within the 5′-flanking region of the endogenous PDX-1 gene: HSS1(−2560~−1880 bp), HSS2(−1330~−800 bp), and HSS3(−260~+180 bp) [38].Among them, HSS1 is an important functional region of PDX-1 gene transcription activation and includes four sub-regions, region I (−2694~−2561 bp), region II (−2139~−1958 bp), and region III (−1879~−1799 bp). The fourth distal enhancer element is region IV, located between −6200 and −5670 bp [39][40][41]. Regions I and II endow endocrine cell expression, region Ⅲ mediates embryonic pancreas-wide expression, and region IV endows pancreas β-cell-specific gene expression and enhancement of proximal enhancer activity [42]. In addition, PDX-1 transcription is also regulated by factors acting upon conserved Area Ⅰ and IV sequences [38]. The proximal and distal promoters contain four conserved regions: I, II, III, and IV, which bind to various transcription factors to regulate cell differentiation [40]. In a study, a child’s pancreas did not develop (pancreatic agenesis) because the child was homozygous for an inactivating cytosine deletion in the protein-coding sequence of PDX-1 (pro63fsdelc), which indicated that PDX-1 might be associated with Type 2 diabetes [43]. In addition, six novel PDX-1 missense mutations (C18R, D76N, R197H, Q59L, G212R and P2390) were identified in patients with type 2 diabetes [44][45].
Biomolecules 12 01785 g001
Figure 1. Structure of PDX-1 gene and protein. (A) PDX-1 gene contains two exons: exon 1 encodes the NH2-terminal domain and some homeodomain of PDX-1 protein, and exon 2 encodes the remaining homeodomain and COOH-terminal domain. Three nuclease-hypersensitive sites were identified within the 5′-flanking region of the endogenous PDX-1 gene: HSS1 (−2560~−1880 bp), HSS2 (−1330~−800 bp) and HSS3 (−260~+180 bp). Among them, HSS1 is an important functional region of PDX-1 gene transcription activation and includes four sub-regions, region I (−2694~−2561 bp), region II (−2139~−1958 bp), region III (−1879~−1799 bp), and region IV (−6200 and −5670 bp). (B) PDX-1 protein comprises 283 amino acids. The NH2-terminal is a proline-rich transcriptional activation domain, including 1~77 amino acids (amino acid AA or aa), which is composed of three highly conserved subdomains A, B, and C (A:13−22aa B:32−38aa C:60−73aa). The homeodomain (HD) is composed of 146~206 amino acids, which contains three highly conserved helical regions: helix1, helix2, and helix3 (H1 H2 H3); the nuclear localization signal (NLS) is part of H3. The COOH-terminal is composed of 238~283 amino acids, and the conserved motif (210~238 amino acids) mediates the interaction of PDX-1-PCIF1 (PDX-1 C-terminal interacting factor-1) and inhibits the transcriptional activity of PDX-1.
The human PDX-1 protein comprises 283 amino acids with a predicted molecular weight of 30.77 KDa [46]. The PDX-1 activation domain is contained within the NH2-terminal, its HD is involved in DNA binding, and they both participate in protein–protein interactions [47]. Point mutation analysis showed that the transcriptional activation region was necessary to activate insulin gene transcription [48]. The HD contains the nuclear localization signal (NLS) and an Antennapedia-like protein transduction domain (PTD), the nuclear import of PDX-1 depends on the NLS motif RRMKWKK [49]. PDX-1 mainly exists in the cytoplasm or around the nucleus in the resting state. Changes in the external environment, such as ionizing radiation and the increase in glucose concentration, can activate PDX-1 and translocate it into the nucleus [50]. The NLS of transcription factors is a crucial requirement for its action, possibly because free PDX-1 is modified by phosphorylation, acetylation, and sumoylation, which exposes the NLS and guides the nuclear translocation of PDX-1 [51][52][53]. In addition, Guillemain G et al. found that PDX-1 first interacts with the nuclear input receptor importinβ1 to form a complex; importinβ1 then interacts with the nuclear pore complex on the nucleus surface. It mediates PDX-1 entry into the nucleus. Ras-related nuclear protein (Ran) GTP and importinβ1 dissociate in the nucleus, followed by the reflux of the Ran GTP and importinβ1 complex into the cytoplasm through nuclear pores. Ran GTP is transformed into Ran, GDP, and the dissociated cytoplasm importinβ1 continues to participate in the transport of transcription factors [54]. In addition, it was previously reported that exogenous PDX-1 protein can permeate cells and induce insulin gene expression in pancreatic ducts because its own antennapedia-like protein transduction domain (PTD) sequence in its structure can bind to the insulin promoter and activate its expression [55]. A conserved motif at the C-terminal of PDX-1 mediates the interaction of PDX-1-PCIF1(PDX-1 C-terminal interacting factor-1) and inhibits the transcriptional activity of PDX-1 [56]. In addition, Humphrey et al. reported a novel functional role for the PDX-1 C-terminus in mediating glucose effects. They demonstrated that glucose modulates PDX-1 stability via the AKT-GSK3 (glycogen synthase kinase 3) axis [57]. Therefore, PDX-1 has a dual function. First, it promotes early pancreatic development and late β-cell differentiation. Second, it maintains the morphology and normal function of mature β cells, especially the normal expression of insulin secretion genes.

2.2. Tissue Distribution and Expression of PDX-1

PDX-1 expression in cells at different stages is inconsistent. In the early developmental stage, PDX-1 widely exists in the cell population transformed into endocrine and exocrine parts of the pancreas and some brain cells in the embryonic stage. However, PDX-1 is highly expressed in β, δ, and endocrine cells of the duodenum following maturation. In contrast, its expression is low in some ductal and acinar cells [58][59]. Stoffers et al. found that PDX-1 played an important role in developing the exocrine and endocrine portions of the pancreas, pancreatic ducts, pyloric glands of the distal stomach, common bile and cystic ducts, the intestinal epithelium of the duodenum, Brunner’s glands, and the spleen [60]. In addition to the gastrointestinal system, PDX-1 is expressed in embryonic brain cells during the active nervous system generation phase [61]. Researchers have reported PDX-1 overexpression in various human tumor tissues [62][63][64]. Wang XP et al. used tissue microarray and immunohistochemical techniques to demonstrate PDX-1 overexpression in breast, kidney, pancreatic, and prostate cancers. They suggested that PDX-1 was probably one of the early markers of tumorigenesis [65].

3. Factors Regulating PDX-1 Expression

PDX-1 is critical for maintaining β cells, and its downregulation results in β-cell dedifferentiation. The induction of PDX-1 expression maintains mature and functional β cells. The regulation of PDX-1 gene expression is a complex process (Figure 2) involving nutrient substances, hormones, oxidative stress, and cytokines.
Biomolecules 12 01785 g002
Figure 2. Model outlining upstream regulator and direct downstream target of PDX-1 and the insulin signaling pathway involved by PDX-1. It has been identified that glucose, lipid, GLP-1, ROS, and other cytokines, such as FoxO1, HNF-3β, HNF-6, PPAR-γ, TGF-β, can directly regulate the expression of PDX-1. PDX-1 regulates the expression of insulin, GCK, GLUT-2, IAPP to maintain β-cell characteristics and functions. In addition, PDX-1 involves the signaling pathway of insulin secretion.

3.1. Nutrient Substances

Glucose and fatty acids regulate PDX-1 expression. Many studies elucidated the underlying molecular mechanisms of glucotoxicity and lipotoxicity. In adult islet β-cell, a short-term hyperglycemic environment promotes the combination of PDX-1 and insulin genes and improves insulin mRNA levels. However, PDX-1 and insulin levels decrease under the cytotoxic effect of long-term hyperglycemia [66]. The inhibition of PDX-1 expression by high glucose concentration is one of the mechanisms of glucotoxicity. Furthermore, chronic hyperglycemia has been reported to deteriorate β-cell function by inducing oxidative stress and reducing PDX-1 DNA-binding activities [67]. In addition to activating the DNA-binding activity of PDX-1, glucose also affects PDX-1 phosphorylation, PDX-1 distribution between the nuclear membrane and nucleoplasm, and the transactivation potential of the amino-terminal active region of PDX-1; however, its mechanism of action remains unclear. High fatty acid concentrations also inhibit PDX-1 expression. Gramlich et al. showed that the co-culture of pancreatic islets with palmitic acid reduced mRNA and protein expression levels of PDX-1 by 70%. The binding force between PDX-1, glucose transporter 2 (GLUT-2), and the insulin gene promoter decreased by 40–65% [68]. The prolonged exposure of islets to palmitate inhibits insulin gene transcription by impairing the nuclear localization of PDX-1 [69]. Shimo N et al. found that PDX-1 expression was significantly reduced during glucotoxicity and lipotoxicity. After treatment with empagliflozin or bezafibrate to selectively improve glucotoxicity or lipotoxicity, PDX-1 showed significantly higher expression levels and enhanced β-cell proliferation [70]. The study provided further evidence that glucose and fatty acids regulate PDX-1 expression.

3.2. Hormones

The incretin hormone glucagon-like peptide-1 (GLP-1) is produced by gut endocrine L cells in a nutrient-dependent manner and secreted in pancreatic islets [71]. Studies have shown that GLP-1 is involved in regulating PDX-1. Wang et al. found that GLP-1 promotes PDX-1 expression in a glucose-dependent manner, increases its intracellular protein content and improves its binding activity with the A1 region of the insulin gene. Simultaneously, GLP-1 activates adenosine cyclase, increases cyclic adenosine monophosphate (cAMP) content in cells, and activates protein kinase A (PKA), which promotes PDX-1 synthesis and increases its content [72][73]. Hwang SL et al. found that treating rat insulinoma cells with GLP-1 significantly increased β-cell translocation gene 2 mRNA expression in dose- and time-dependent manners and subsequently elevated PDX-1 and insulin mRNA levels in pancreatic β cells [74]. The activation of PKA induced by GLP-1 increases PDX-1 level and translocation to the nucleus, where PDX-1 binds to the insulin gene promoter to initiate insulin expression and synthesis [75]. In addition, the runaway signal system of the small Ran GTPase significantly downregulates PDX-1 expression in postnatal mice, resulting in insulin deficiency, decreased cell proliferation rate, and diabetes [76]. In aging animal models of type 2 diabetes, the expression of the PDX-1 gene was decreased, the number of β cells was reduced, and the long-term use of GLP-1 reversed these pathological changes. However, when exendin (9–39) (a specific antagonist of GLP-1) was infused, its effects on the levels of PDX-1 messenger RNA were eliminated [77]. These studies showed that GLP-1 stimulates pancreatic cell proliferation and β-cell differentiation by regulating PDX-1.

3.3. Oxidative Stress

Some studies have shown that reactive oxygen species (ROS) reduce PDX-1 mRNA synthesis, leading to a decline in PDX-1 synthesis and a reduction in the binding of PDX-1 to the insulin gene promoter and the transcription of the insulin gene. Cannabinoids have strong antioxidant properties. Baeeri et al. used 10 μM cannabidiol and tetrahydrocannabinol to treat aged rat islet cells. The results showed that the percentage of ROS was significantly reduced with the elevation of PDX-1 expression and insulin release [78]. However, the results were preliminary, and further studies are needed to elucidate the mechanism. Leenders et al. treated human islets with 200 μM hydrogen peroxide for 90 min and found that the gene and protein expression of the key transcription factor PDX-1 was reduced by over 60% [79]. Furthermore, Matsuoka et al. treated HIT-T15 cells cultured in vitro with the oxidative stress inducer d-ribose. They found that PDX-1 expression in cells was reduced, and the binding of PDX-1 to the insulin gene promoter was significantly reduced. However, 1 mM aminoguanidine or 10 mM N-acetyl-L-cysteine (NAC) prevented the effects of d-ribose [80]. Kawamori et al. also found that oxidative stress affects the nucleocytoplasmic translocation of PDX-1 by activating c-Jun N-terminal kinase (JNK) and pointed out that JNK may induce the translocation of PDX-1 from the nucleus to the cytoplasm by activating the nuclear output signal of PDX-1, reducing the expression of PDX-1 in the nucleus, and also reducing insulin synthesis and secretion [81][82]. After treating diabetes mice (C57BL/KsJ-db/db) with antioxidant drugs (NAC), Kajimoto et al. found that the expression of PDX-1 in the nucleus of pancreatic islets was significantly increased, and the amounts of insulin content and insulin mRNA were preserved [83]. Nucleocytoplasmic translocation of PDX-1 is the key to promoting insulin secretion. Oxidative stress can affect the nucleocytoplasmic translocation of PDX-1, reduce the interaction between PDX-1 and insulin gene promoters, and reduce insulin synthesis and secretion. Baumel-Alterzon S et al. reported that the nuclear factor erythroid 2-related factor (Nrf2) antioxidant pathway controls the redox balance and allows the maintenance of high PDX-1 levels; pharmacological activation of the Nrf2 pathway may alleviate diabetes by preserving PDX-1 levels [84].

3.4. Cytokines

Many cytokines (hepatocyte nuclear factor (HNF-3β), HNF-6, transforming growth factor-beta (TGF-β), peroxisome proliferator-activated receptor gamma (PPAR-γ)) act upstream of PDX-1 in the regulatory hierarchy governing pancreatic development. HNF-3β (also named Foxa2) is a transcription factor in the HNF family. HNF-3β binds to multiple sites in the transcriptional activation functional region of the PDX-1 gene and recruits other transcription factors to the regulatory region to enhance gene transcription [85]. In addition, co-transfection experiments suggested that HNF-3β, HNF-1α, and specificity protein 1 (Sp1) are positive human PDX-1 enhancer elements with mutual coordination [86]. Gao et al. found that compound conditional ablation of Foxa1 and Foxa2 caused near severe pancreatic hypoplasia and total loss of PDX-1 expression, and Foxa2 appeared to predominate. Jacquemin et al. also found that HNF-6 acted upstream of PDX-1 during the development of the pancreas, and HNF-6(-/-) mice were hypoplastic [87]. Sayo et al. used the TGF-β to process pancreatic β cells, and the results showed that TGF-β activates the insulin gene by activating PDX-1 [88]. PPAR-γ agonist rosiglitazone was reported to increase the immunostaining of PDX-1 and Nkx6.1, while PPAR-γ inhibitors reduced the mRNA levels of PDX-1 through RNA interference [89]. In addition, the study found that PDX-1 interacted with the p300 coactivator, β-cell E-box transcription factor (BETA2), and E47 coactivator to mediate insulin gene transcription [58]. These cytokines play a significant role in developing the pancreas; however, further studies are needed to explore their regulation to ensure PDX-1 transcription.

References

  1. Vieira, R.; Souto, S.B.; Sánchez-López, E.; Machado, A.L.; Severino, P.; Jose, S.; Santini, A.; Fortuna, A.; García, M.L.; Silva, A.M.; et al. Sugar-Lowering Drugs for Type 2 Diabetes Mellitus and Metabolic Syndrome-Review of Classical and New Compounds: Part-I. Pharmaceuticals 2019, 12, 152.
  2. IDF Diabetes Atlas. Idf Diabetes Atlas; International Diabetes Federation: Brussels, Belgium, 2021.
  3. Bjornstad, P.; Drews, K.; Zeitler, P.S. Long-Term Complications in Youth-Onset Type 2 Diabetes. Reply. N. Engl. J. Med. 2021, 385, 2016.
  4. Bolli, G.B.; Gerich, J.E. The “dawn phenomenon”—A common occurrence in both non-insulin-dependent and insulin-dependent diabetes mellitus. N. Engl. J. Med. 1984, 310, 746–750.
  5. American Diabetes Association Professional Practice Committee. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2022. Diabetes Care 2022, 45 (Suppl. 1), S17–S38.
  6. Sperling, M.A.; Laffel, L.M. Current Management of Glycemia in Children with Type 1 Diabetes Mellitus. N. Engl. J. Med. 2022, 386, 1155–1164.
  7. Syed, F.Z. Type 1 Diabetes Mellitus. Ann. Intern. Med. 2022, 175, Itc33–Itc48.
  8. Demir, S.; Nawroth, P.P.; Herzig, S.; Ekim Üstünel, B. Emerging Targets in Type 2 Diabetes and Diabetic Complications. Adv. Sci. 2021, 8, e2100275.
  9. Prasad, R.B.; Groop, L. Genetics of type 2 diabetes-pitfalls and possibilities. Genes 2015, 6, 87–123.
  10. Liu, J.; Lang, G.; Shi, J. Epigenetic Regulation of PDX-1 in Type 2 Diabetes Mellitus. Diabetes Metab. Syndr. Obes. Targets Ther. 2021, 14, 431–442.
  11. Kahn, S.E.; Cooper, M.E.; Del Prato, S. Pathophysiology and treatment of type 2 diabetes: Perspectives on the past, present, and future. Lancet 2014, 383, 1068–1083.
  12. Rines, A.K.; Sharabi, K.; Tavares, C.D.; Puigserver, P. Targeting hepatic glucose metabolism in the treatment of type 2 diabetes. Nat. Rev. Drug Discov. 2016, 15, 786–804.
  13. Riddle, M.C.; Cefalu, W.T.; Evans, P.H.; Gerstein, H.C.; Nauck, M.A.; Oh, W.K.; Rothberg, A.E.; le Roux, C.W.; Rubino, F.; Schauer, P.; et al. Consensus Report: Definition and Interpretation of Remission in Type 2 Diabetes. Diabetes Care 2021, 44, 2438–2444.
  14. Taylor, R.; Al-Mrabeh, A.; Sattar, N. Understanding the mechanisms of reversal of type 2 diabetes. Lancet Diabetes Endocrinol. 2019, 7, 726–736.
  15. Al-Mrabeh, A.; Zhyzhneuskaya, S.V.; Peters, C.; Barnes, A.C.; Melhem, S.; Jesuthasan, A.; Aribisala, B.; Hollingsworth, K.G.; Lietz, G.; Mathers, J.C.; et al. Hepatic Lipoprotein Export and Remission of Human Type 2 Diabetes after Weight Loss. Cell Metab. 2020, 31, 233–249.e234.
  16. Wang, Z.; Xiong, H.; Ren, T.Y.S. Repair of Damaged Pancreatic β Cells: New Hope for a Type 2 Diabetes Reversal? J. Transl. Int. Med. 2021, 9, 150–151.
  17. Singla, R.; Gupta, G.; Dutta, D.; Raizada, N.; Aggarwal, S. Diabetes reversal: Update on current knowledge and proposal of prediction score parameters for diabetes remission. Diabetes Metab. Syndr. 2022, 16, 102452.
  18. Leonard, J.; Peers, B.; Johnson, T.; Ferreri, K.; Lee, S.; Montminy, M.R. Characterization of somatostatin transactivating factor-1, a novel homeobox factor that stimulates somatostatin expression in pancreatic islet cells. Mol. Endocrinol. 1993, 7, 1275–1283.
  19. Jonsson, J.; Carlsson, L.; Edlund, T.; Edlund, H. Insulin-promoter-factor 1 is required for pancreas development in mice. Nature 1994, 371, 606–609.
  20. Dutta, S.; Bonner-Weir, S.; Montminy, M.; Wright, C. Regulatory factor linked to late-onset diabetes? Nature 1998, 392, 560.
  21. Ferber, S.; Halkin, A.; Cohen, H.; Ber, I.; Einav, Y.; Goldberg, I.; Barshack, I.; Seijffers, R.; Kopolovic, J.; Kaiser, N.; et al. Pancreatic and duodenal homeobox gene 1 induces expression of insulin genes in liver and ameliorates streptozotocin-induced hyperglycemia. Nat. Med. 2000, 6, 568–572.
  22. Noguchi, H.; Kaneto, H.; Weir, G.C.; Bonner-Weir, S. PDX-1 protein containing its own antennapedia-like protein transduction domain can transduce pancreatic duct and islet cells. Diabetes 2003, 52, 1732–1737.
  23. Holland, A.M.; Góñez, L.J.; Naselli, G.; Macdonald, R.J.; Harrison, L.C. Conditional expression demonstrates the role of the homeodomain transcription factor Pdx1 in maintenance and regeneration of beta-cells in the adult pancreas. Diabetes 2005, 54, 2586–2595.
  24. Spaeth, J.M.; Gupte, M.; Perelis, M.; Yang, Y.P.; Cyphert, H.; Guo, S.; Liu, J.H.; Guo, M.; Bass, J.; Magnuson, M.A.; et al. Defining a Novel Role for the Pdx1 Transcription Factor in Islet β-Cell Maturation and Proliferation During Weaning. Diabetes 2017, 66, 2830–2839.
  25. Xiao, X.; Guo, P.; Shiota, C.; Zhang, T.; Coudriet, G.M.; Fischbach, S.; Prasadan, K.; Fusco, J.; Ramachandran, S.; Witkowski, P.; et al. Endogenous Reprogramming of Alpha Cells into Beta Cells, Induced by Viral Gene Therapy, Reverses Autoimmune Diabetes. Cell Stem Cell 2018, 22, 78–90.e74.
  26. Furuyama, K.; Chera, S.; van Gurp, L.; Oropeza, D.; Ghila, L.; Damond, N.; Vethe, H.; Paulo, J.A.; Joosten, A.M.; Berney, T.; et al. Diabetes relief in mice by glucose-sensing insulin-secreting human α-cells. Nature 2019, 567, 43–48.
  27. Stoffers, D.A.; Zinkin, N.T.; Stanojevic, V.; Clarke, W.L.; Habener, J.F. Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat. Genet. 1997, 15, 106–110.
  28. Gao, T.; McKenna, B.; Li, C.; Reichert, M.; Nguyen, J.; Singh, T.; Yang, C.; Pannikar, A.; Doliba, N.; Zhang, T.; et al. Pdx1 maintains β cell identity and function by repressing an α cell program. Cell Metab. 2014, 19, 259–271.
  29. Scott, V.; Clark, A.R.; Hutton, J.C.; Docherty, K. Two proteins act as the IUF1 insulin gene enhancer binding factor. FEBS Lett. 1991, 290, 27–30.
  30. Ohlsson, H.; Karlsson, K.; Edlund, T. IPF1, a homeodomain-containing transactivator of the insulin gene. EMBO J. 1993, 12, 4251–4259.
  31. Miller, C.P.; McGehee, R.E., Jr.; Habener, J.F. IDX-1: A new homeodomain transcription factor expressed in rat pancreatic islets and duodenum that transactivates the somatostatin gene. EMBO J. 1994, 13, 1145–1156.
  32. Wright, C.V.; Schnegelsberg, P.; De Robertis, E.M. XlHbox 8: A novel Xenopus homeo protein restricted to a narrow band of endoderm. Development 1989, 105, 787–794.
  33. Yokoi, N.; Serikawa, T.; Walther, R. Pdx1, a homeodomain transcription factor required for pancreas development, maps to rat chromosome 12. Exp. Anim. 1997, 46, 323–324.
  34. Sharma, S.; Leonard, J.; Lee, S.; Chapman, H.D.; Leiter, E.H.; Montminy, M.R. Pancreatic islet expression of the homeobox factor STF-1 relies on an E-box motif that binds USF. J. Biol. Chem. 1996, 271, 2294–2299.
  35. Stoffel, M.; Stein, R.; Wright, C.V.; Espinosa, R., 3rd; Le Beau, M.M.; Bell, G.I. Localization of human homeodomain transcription factor insulin promoter factor 1 (IPF1) to chromosome band 13q12.1. Genomics 1995, 28, 125–126.
  36. Inoue, H.; Riggs, A.C.; Tanizawa, Y.; Ueda, K.; Kuwano, A.; Liu, L.; Donis-Keller, H.; Permutt, M.A. Isolation, characterization, and chromosomal mapping of the human insulin promoter factor 1 (IPF-1) gene. Diabetes 1996, 45, 789–794.
  37. Melloul, D.; Marshak, S.; Cerasi, E. Regulation of pdx-1 gene expression. Diabetes 2002, 51 (Suppl. 3), S320–S325.
  38. Wu, K.L.; Gannon, M.; Peshavaria, M.; Offield, M.F.; Henderson, E.; Ray, M.; Marks, A.; Gamer, L.W.; Wright, C.V.; Stein, R. Hepatocyte nuclear factor 3beta is involved in pancreatic beta-cell-specific transcription of the pdx-1 gene. Mol. Cell. Biol. 1997, 17, 6002–6013.
  39. Gerrish, K.; Gannon, M.; Shih, D.; Henderson, E.; Stoffel, M.; Wright, C.V.E.; Stein, R. Pancreatic beta cell-specific transcription of the pdx-1 gene. The role of conserved upstream control regions and their hepatic nuclear factor 3beta sites. J. Biol. Chem. 2000, 275, 3485–3492.
  40. Gerrish, K.; Van Velkinburgh, J.C.; Stein, R. Conserved transcriptional regulatory domains of the pdx-1 gene. Mol. Endocrinol. 2004, 18, 533–548.
  41. Samaras, S.E.; Cissell, M.A.; Gerrish, K.; Wright, C.V.E.; Gannon, M.; Stein, R. 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. 2002, 22, 4702–4713.
  42. Wiebe, P.O.; Kormish, J.D.; Roper, V.T.; Fujitani, Y.; Alston, N.I.; Zaret, K.S.; Wright, C.V.E.; Stein, R.W.; Gannon, M. Ptf1a binds to and activates area III, a highly conserved region of the Pdx1 promoter that mediates early pancreas-wide Pdx1 expression. Mol. Cell. Biol. 2007, 27, 4093–4104.
  43. Stoffers, D.; Stanojevic, V.; Habener, J.F. Insulin promoter factor-1 gene mutation linked to early-onset type 2 diabetes mellitus directs expression of a dominant negative isoprotein. J. Clin. Investig. 1998, 102, 232–241.
  44. Macfarlane, W.M.; Frayling, T.; Ellard, S.; Evans, J.C.; Allen, L.I.; Bulman, M.P.; Ayres, S.; Shepherd, M.; Clark, P.; Millward, A.; et al. Missense mutations in the insulin promoter factor-1 gene predispose to type 2 diabetes. J. Clin. Investig. 1999, 104, R33–R39.
  45. Weng, J.; Macfarlane, W.M.; Lehto, M.; Gu, H.F.; Shepherd, L.M.; Ivarsson, S.A.; Wibell, L.; Smith, T.; Groop, L.C. Functional consequences of mutations in the MODY4 gene (IPF1) and coexistence with MODY3 mutations. Diabetologia 2001, 44, 249–258.
  46. McKinnon, C.M.; Docherty, K. Pancreatic duodenal homeobox-1, PDX-1, a major regulator of beta cell identity and function. Diabetologia 2001, 44, 1203–1214.
  47. Qiu, Y.; Guo, M.; Huang, S.; Stein, R. Insulin gene transcription is mediated by interactions between the p300 coactivator and PDX-1, BETA2, and E47. Mol. Cell Biol. 2002, 22, 412–420.
  48. Hui, H.; Perfetti, R. Pancreas duodenum homeobox-1 regulates pancreas development during embryogenesis and islet cell function in adulthood. Eur. J. Endocrinol. 2002, 146, 129–141.
  49. Moede, T.; Leibiger, B.; Pour, H.G.; Berggren, P.; Leibiger, I.B. Identification of a nuclear localization signal, RRMKWKK, in the homeodomain transcription factor PDX-1. FEBS Lett. 1999, 461, 229–234.
  50. Macfarlane, W.M.; McKinnon, C.M.; Felton-Edkins, Z.A.; Cragg, H.; James, R.F.; Docherty, K. Glucose stimulates translocation of the homeodomain transcription factor PDX1 from the cytoplasm to the nucleus in pancreatic beta-cells. J. Biol. Chem. 1999, 274, 1011–1016.
  51. Elrick, L.J.; Docherty, K. Phosphorylation-dependent nucleocytoplasmic shuttling of pancreatic duodenal homeobox-1. Diabetes 2001, 50, 2244–2252.
  52. Kishi, A.; Nakamura, T.; Nishio, Y.; Maegawa, H.; Kashiwagi, A. Sumoylation of Pdx1 is associated with its nuclear localization and insulin gene activation. Am. J. Physiol. Endocrinol. Metab. 2003, 284, E830–E840.
  53. Hessabi, B.; Ziegler, P.; Schmidt, I.; Hessabi, C.; Walther, R. The nuclear localization signal (NLS) of PDX-1 is part of the homeodomain and represents a novel type of NLS. Eur. J. Biochem. 1999, 263, 170–177.
  54. Guillemain, G.; Da Silva Xavier, G.; Rafiq, I.; Leturque, A.; Rutter, G.A. Importin beta1 mediates the glucose-stimulated nuclear import of pancreatic and duodenal homeobox-1 in pancreatic islet beta-cells (MIN6). Biochem. J. 2004, 378, 219–227.
  55. Noguchi, H.; Matsushita, M.; Matsumoto, S.; Lu, Y.-F.; Matsui, H.; Bonner-Weir, S. Mechanism of PDX-1 protein transduction. Biochem. Biophys. Res. Commun. 2005, 332, 68–74.
  56. Liu, A.; Desai, B.M.; Stoffers, D.A. Identification of PCIF1, a POZ domain protein that inhibits PDX-1 (MODY4) transcriptional activity. Mol. Cell Biol. 2004, 24, 4372–4383.
  57. Humphrey, R.K.; Yu, S.M.; Flores, L.E.; Jhala, U.S. Glucose regulates steady-state levels of PDX1 via the reciprocal actions of GSK3 and AKT kinases. J. Biol. Chem. 2010, 285, 3406–3416.
  58. Guz, Y.; Montminy, M.R.; Stein, R.; Leonard, J.; Gamer, L.W.; Wright, C.V.; Teitelman, G. Expression of murine STF-1, a putative insulin gene transcription factor, in beta cells of pancreas, duodenal epithelium and pancreatic exocrine and endocrine progenitors during ontogeny. Development 1995, 121, 11–18.
  59. Sander, M.; German, M.S. The beta cell transcription factors and development of the pancreas. J. Mol. Med. 1997, 75, 327–340.
  60. Stoffers, D.A.; Heller, R.S.; Miller, C.P.; Habener, J.F. Developmental expression of the homeodomain protein IDX-1 in mice transgenic for an IDX-1 promoter/lacZ transcriptional reporter. Endocrinology 1999, 140, 5374–5381.
  61. Perez-Villamil, B.; Schwartz, P.T.; Vallejo, M. The pancreatic homeodomain transcription factor IDX1/IPF1 is expressed in neural cells during brain development. Endocrinology 1999, 140, 3857–3860.
  62. Sakai, H.; Eishi, Y.; Li, X.L.; Akiyama, Y.; Miyake, S.; Takizawa, T.; Konishi, N.; Tatematsu, M.; Koike, M.; Yuasa, Y. PDX1 homeobox protein expression in pseudopyloric glands and gastric carcinomas. Gut 2004, 53, 323–330.
  63. Ballian, N.; Liu, S.H.; Brunicardi, F.C. Transcription factor PDX-1 in human colorectal adenocarcinoma: A potential tumor marker? World J. Gastroenterol. 2008, 14, 5823–5826.
  64. Liu, T.; Gou, S.M.; Wang, C.Y.; Wu, H.S.; Xiong, J.X.; Zhou, F. Pancreas duodenal homeobox-1 expression and significance in pancreatic cancer. World J. Gastroenterol. 2007, 13, 2615–2618.
  65. Wang, X.P.; Li, Z.J.; Magnusson, J.; Brunicardi, F.C. Tissue MicroArray analyses of pancreatic duodenal homeobox-1 in human cancers. World J. Surg. 2005, 29, 334–338.
  66. Evans-Molina, C.; Garmey, J.C.; Ketchum, R.; Brayman, K.L.; Deng, S.; Mirmira, R.G. Glucose regulation of insulin gene transcription and pre-mRNA processing in human islets. Diabetes 2007, 56, 827–835.
  67. Ahlgren, U.; Jonsson, J.; Jonsson, L.; Simu, K.; Edlund, H. beta-cell-specific inactivation of the mouse Ipf1/Pdx1 gene results in loss of the beta-cell phenotype and maturity onset diabetes. Genes Dev. 1998, 12, 1763–1768.
  68. Gremlich, S.; Bonny, C.; Waeber, G.; Thorens, B. Fatty acids decrease IDX-1 expression in rat pancreatic islets and reduce GLUT2, glucokinase, insulin, and somatostatin levels. J. Biol. Chem. 1997, 272, 30261–30269.
  69. Hagman, D.K.; Hays, L.B.; Parazzoli, S.D.; Poitout, V. Palmitate inhibits insulin gene expression by altering PDX-1 nuclear localization and reducing MafA expression in isolated rat islets of Langerhans. J. Biol. Chem. 2005, 280, 32413–32418.
  70. Shimo, N.; Matsuoka, T.A.; Miyatsuka, T.; Takebe, S.; Tochino, Y.; Takahara, M.; Kaneto, H.; Shimomura, I. Short-term selective alleviation of glucotoxicity and lipotoxicity ameliorates the suppressed expression of key β-cell factors under diabetic conditions. Biochem. Biophys. Res. Commun. 2015, 467, 948–954.
  71. McLean, B.A.; Wong, C.K.; Campbell, J.E.; Hodson, D.J.; Trapp, S.; Drucker, D.J. Revisiting the Complexity of GLP-1 Action from Sites of Synthesis to Receptor Activation. Endocr. Rev. 2021, 42, 101–132.
  72. Wang, X.; Zhou, J.; Doyle, M.E.; Egan, J.M. Glucagon-like peptide-1 causes pancreatic duodenal homeobox-1 protein translocation from the cytoplasm to the nucleus of pancreatic beta-cells by a cyclic adenosine monophosphate/protein kinase A-dependent mechanism. Endocrinology 2001, 142, 1820–1827.
  73. Wang, X.; Cahill, C.M.; Piñeyro, M.A.; Zhou, J.; Doyle, M.E.; Egan, J.M. Glucagon-like peptide-1 regulates the beta cell transcription factor, PDX-1, in insulinoma cells. Endocrinology 1999, 140, 4904–4907.
  74. Hwang, S.L.; Kwon, O.; Kim, S.G.; Lee, I.K.; Kim, Y.D. B-cell translocation gene 2 positively regulates GLP-1-stimulated insulin secretion via induction of PDX-1 in pancreatic β-cells. Exp. Mol. Med. 2013, 45, e25.
  75. Müller, T.D.; Finan, B.; Bloom, S.R.; D’Alessio, D.; Drucker, D.J.; Flatt, P.R.; Fritsche, A.; Gribble, F.; Grill, H.J.; Habener, J.F.; et al. Glucagon-like peptide 1 (GLP-1). Mol. Metab. 2019, 30, 72–130.
  76. Xia, F.; Dohi, T.; Martin, N.M.; Raskett, C.M.; Liu, Q.; Altieri, D.C. Essential role of the small GTPase Ran in postnatal pancreatic islet development. PLoS ONE 2011, 6, e27879.
  77. Perfetti, R.; Zhou, J.; Doyle, M.E.; Egan, J.M. Glucagon-like peptide-1 induces cell proliferation and pancreatic-duodenum homeobox-1 expression and increases endocrine cell mass in the pancreas of old, glucose-intolerant rats. Endocrinology 2000, 141, 4600–4605.
  78. Baeeri, M.; Rahimifard, M.; Daghighi, S.M.; Khan, F.; Salami, S.A.; Moini-Nodeh, S.; Haghi-Aminjan, H.; Bayrami, Z.; Rezaee, F.; Abdollahi, M. Cannabinoids as anti-ROS in aged pancreatic islet cells. Life Sci. 2020, 256, 117969.
  79. Leenders, F.; Groen, N.; de Graaf, N.; Engelse, M.A.; Rabelink, T.J.; de Koning, E.J.P.; Carlotti, F. Oxidative Stress Leads to β-Cell Dysfunction Through Loss of β-Cell Identity. Front. Immunol. 2021, 12, 690379.
  80. Matsuoka, T.; Kajimoto, Y.; Watada, H.; Kaneto, H.; Kishimoto, M.; Umayahara, Y.; Fujitani, Y.; Kamada, T.; Kawamori, R.; Yamasaki, Y. Glycation-dependent, reactive oxygen species-mediated suppression of the insulin gene promoter activity in HIT cells. J. Clin. Investig. 1997, 99, 144–150.
  81. Kawamori, D.; Kajimoto, Y.; Kaneto, H.; Umayahara, Y.; Fujitani, Y.; Miyatsuka, T.; Watada, H.; Leibiger, I.B.; Yamasaki, Y.; Hori, M. Oxidative stress induces nucleo-cytoplasmic translocation of pancreatic transcription factor PDX-1 through activation of c-Jun NH(2)-terminal kinase. Diabetes 2003, 52, 2896–2904.
  82. Liang, H.; Pan, Y.; Teng, Y.; Yuan, S.; Wu, X.; Yang, H.; Zhou, P. A proteoglycan extract from Ganoderma Lucidum protects pancreatic beta-cells against STZ-induced apoptosis. Biosci. Biotechnol. Biochem. 2020, 84, 2491–2498.
  83. Kaneto, H.; Kajimoto, Y.; Miyagawa, J.; Matsuoka, T.; Fujitani, Y.; Umayahara, Y.; Hanafusa, T.; Matsuzawa, Y.; Yamasaki, Y.; Hori, M. Beneficial effects of antioxidants in diabetes: Possible protection of pancreatic beta-cells against glucose toxicity. Diabetes 1999, 48, 2398–2406.
  84. Baumel-Alterzon, S.; Scott, D.K. Regulation of Pdx1 by oxidative stress and Nrf2 in pancreatic beta-cells. Front. Endocrinol. 2022, 13, 1011187.
  85. Gao, N.; LeLay, J.; Vatamaniuk, M.Z.; Rieck, S.; Friedman, J.R.; Kaestner, K.H. Dynamic regulation of Pdx1 enhancers by Foxa1 and Foxa2 is essential for pancreas development. Genes Dev. 2008, 22, 3435–3448.
  86. Marshak, S.; Benshushan, E.; Shoshkes, M.; Havin, L.; Cerasi, E.; Melloul, D. Functional conservation of regulatory elements in the pdx-1 gene: PDX-1 and hepatocyte nuclear factor 3beta transcription factors mediate beta-cell-specific expression. Mol. Cell Biol. 2000, 20, 7583–7590.
  87. Jacquemin, P.; Lemaigre, F.P.; Rousseau, G.G. The Onecut transcription factor HNF-6 (OC-1) is required for timely specification of the pancreas and acts upstream of Pdx-1 in the specification cascade. Dev. Biol. 2003, 258, 105–116.
  88. Sayo, Y.; Hosokawa, H.; Imachi, H.; Murao, K.; Sato, M.; Wong, N.C.; Ishida, T.; Takahara, J. Transforming growth factor beta induction of insulin gene expression is mediated by pancreatic and duodenal homeobox gene-1 in rat insulinoma cells. Eur. J. Biochem. 2000, 267, 971–978.
  89. Moibi, J.A.; Gupta, D.; Jetton, T.L.; Peshavaria, M.; Desai, R.; Leahy, J.L. Peroxisome proliferator-activated receptor-gamma regulates expression of PDX-1 and NKX6.1 in INS-1 cells. Diabetes 2007, 56, 88–95.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Others
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Yanjiao Zhang
,
Xinyi Fang
,
Jiahua Wei
,
Runyu Miao
,
Haoran Wu
,
Kaile Ma
,
Jiaxing Tian
View Times: 564
Revisions: 2 times (View History)
Update Date: 21 Dec 2022
Table of Contents
    1000/1000
    Hot Most Recent
    Academic Video Service
    Feedback