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Review
. 2022 Nov 30;12(12):1785.
doi: 10.3390/biom12121785.

PDX-1: A Promising Therapeutic Target to Reverse Diabetes

Yanjiao Zhang  1 , Xinyi Fang  1   2 , Jiahua Wei  3 , Runyu Miao  1   2 , Haoran Wu  2 , Kaile Ma  1 , Jiaxing Tian  1
Affiliations
Review

PDX-1: A Promising Therapeutic Target to Reverse Diabetes

Yanjiao Zhang et al. Biomolecules. .

Abstract

The pancreatic duodenum homeobox-1 (PDX-1) is a transcription factor encoded by a Hox-like homeodomain gene that plays a crucial role in pancreatic development, β-cell differentiation, and the maintenance of mature β-cell functions. Research on the relationship between PDX-1 and diabetes has gained much attention because of the increasing prevalence of diabetes melitus (DM). Recent studies have shown that the overexpression of PDX-1 regulates pancreatic development and promotes β-cell differentiation and insulin secretion. It also plays a vital role in cell remodeling, gene editing, and drug development. Conversely, the absence of PDX-1 increases susceptibility to DM. Therefore, in this review, we summarized the role of PDX-1 in pancreatic development and the pathogenesis of DM. A better understanding of PDX-1 will deepen our knowledge of the pathophysiology of DM and provide a scientific basis for exploring PDX-1 as a potential target for treating diabetes.

Keywords: PDX-1; diabetes mellitus; reversal; transcription factor; β-cell.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
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.
Figure 2
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.
Figure 3
Figure 3
Schematic representation of the PDX-1 involved in the development of the pancreas and the differentiation of islet cells. During embryogenesis, the pancreas arises from the foregut of the endoderm in the area that will become the duodenum. PDX-1 is essential for pancreatic development and β-cell differentiation. It is expressed in both endocrine cells and exocrine cells before maturation and is first detected in the gut’s dorsal region at embryonic days (e8.5). At e9.5, its expression is localized to the dorsal and ventral buds concomitantly with the first glucagon-secreting α cells. At e10.5, insulin-producing β-cell appear, and PDX-1 is a marker of β-cell formation and maturation. At e15.5, PDX-1 specifically expressed in δ cells and PP cells. With the development of the pancreas, PDX-1 is only specifically distributed in β cells and δ cells.
Figure 4
Figure 4
The regulation of insulin expression gene and formation of transcription activation complex. PDX-1 can bind to the A3 and A4 (collectively referred to as A3/4) sites and activate the E2A3/4 mini-enhancer by synergizing with E47 bound to the E2 site. PDX-1 and E47 do not activate the E2A3/4 mini-enhancer either individually or together. The addition of high-mobility group protein I(Y) (HMG I(Y)) allows for strong cooperative activation of the mini-enhancer by the three proteins together, but only if both the E and the A binding sites are intact in the mini-enhancer. Beta2 and HMG I(Y) contribute to PDX-1–E47 synergy through direct interactions with the homeodomain of PDX-1. The homeodomain of PDX-1 acts as a protein–protein interaction domain to recruit multiple proteins, including E47, Beta2, and HMG I(Y), to an activation complex on the E2A3/4 mini-enhancer. The p300 coactivator interacted with the activation domains of Beta2 and E47 both physically and functionally.
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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. doi: 10.3390/ph12040152. - DOI - PMC - PubMed
    1. IDF Diabetes Atlas . Idf Diabetes Atlas. International Diabetes Federation; Brussels, Belgium: 2021.
    1. Bjornstad P., Drews K., Zeitler P.S. Long-Term Complications in Youth-Onset Type 2 Diabetes. Reply. N. Engl. J. Med. 2021;385:2016. doi: 10.1056/NEJMc2114053. - DOI - PMC - PubMed
    1. 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. doi: 10.1056/NEJM198403223101203. - DOI - PubMed
    1. 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. doi: 10.2337/dc22-S002. - DOI - PubMed

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