Biomolecules, Vol. 12, Pages 1785: PDX-1: A Promising Therapeutic Target to Reverse Diabetes

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 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.

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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 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.

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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 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.

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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.

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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Table 1. The upstream and downstream targets of PDX-1.

Table 1. The upstream and downstream targets of PDX-1.

UpstreamDownstream1glucoseinsulin2lipidGCK3GLP-1GLUT-24ROSIAPP5HNF-3βsomatostatin6HNF-6Ngn37TGF-βInsm28PPAR-γsynaptophysin9HNF-1αPax410Sp1MafA11HMGA1Nkx6.112FoxO1 13Foxa1 14Foxa2 15PKA 16c-JUN 17JNK

Table 2. Representative potential PDX-1 inducing drugs, small molecules and natural compounds.

Table 2. Representative potential PDX-1 inducing drugs, small molecules and natural compounds.

NumberNameExperimental ModelAdministration DoseDrug EffectReference1Swietenine (Stn) and swietenolide (Std)INS-1 cells (Procell CL-0368)2 μM, 5 μM, 8 μM, 10 μM, 15 μM, 20 μM, 30 μM, 40 μM, 50 μMIt up-regulates the expression of PDX-1 protein, improves the insulin secretion function, protects oxidative stress injury, and reduces apoptosis.[150]2Loureirin B3-week-old male C57BL/6J mice (14–15 g)45 mg/kg i.g.It activates the AKT/PDX-1 signaling pathway.[151]3Medicago sativa L.Bone marrow mesenchymal stem cells (MSCs)50 μg/mLIt has the potential of differentiation induction of MSCs into IPCs with the characteristics of pancreatic β-like cells.[152]4Nigella sativa seedMale diabetic Wistar rats200 mg/kg, 400 mg/kg p.o.It reduces oxidative stress and tissue damage, modifies the expression levels of PDX-1 and MafA genes, and regulates insulin secretion and blood glucose levels.[153]5HDPs-2A (a polysaccharide purified from Hovenia dulcis)7-week-old male Sprague Dawley (SD) rats (170 ± 10 g)300 mg/kg, 200 mg/kg, 100 mg/kg, p.o.It up-regulates PDX-1, activates and up-regulates IRS2 expression, and regulates apoptosis and regeneration of islet β cells to recover islet β-cell function injury in TIDM rats.[154]6Thiamine disulfide (TD)4-week-old male Wistar rats (180–250 g)40 mg/kg i.p.It increases serum insulin levels, IIR, and expression of PDX-1 and GLUT-2 genes.[155]7Gymnemic acid (GA)2-month-old male albino Wistar rats (130–150 g)150 mg/kg p.o.It ameliorates pancreatic β-cell dysfunction by modulating PDX-1 expression.[156]8CordycepinINS-1 cells0.5~20 μMIt upregulates the mRNA level and protein expression of insulin, PDX-1, and GLUT-1.[157]9Carnosic acid (CA)INS-1 cells2.5 μM, 5 μM, 10 μMIt can protect β-cells through the PI3K/AKT/PDX-1/insulin pathway and mitochondria-mediated apoptosis.[158]10Icariin6-week-old male albino rats (170–200 g)100 mg/kg p.o.Icariin, and/or MSCs promoted the regeneration of pancreatic tissues by releasing PDX-1 and MafA involved in the recruitment of stem/progenitor cells in the tissue.[159]11HesperidinMale Sprague Dawley rats100 mg·kg−1 p.o.It enhances β-cell proliferation and repair and raises serum insulin levels.[160]12A new form of silymarin solution (NFSM)Male Wistar rats (220–250 g)100 mg/kg p.o.It increases the expression of PDX-1 and insulin genes.[161]13Oligosaccharide fraction isolated from Rosa canina8-week-old male Wistar rats (200–250 g)10, 20 and 30 mg/kg i.g.It increases the expression of PDX-1 and may contribute to the modulation of DNA methylation.[162]14Andrographolide named C10378-week-old male Kunming mice (18–22 g)50 mg/kg i.g.It promotes pancreatic duct cell differentiation into insulin-producing cells by targeting PDX-1.[149]15TectorigeninINS-1 cells;Diet-induced obese C57BL/6J mice40 μg/mL; 10, 20, 40 mg/kg i.p.It enhances PDX-1 expression and protects pancreatic β-cells by activating ERK and reducing ER stress.[145]16Stigmasterol-3-O-β-d-glucosideINS-1 cells5 μM,10 μMIt enhances the PI3K-dependent phosphorylation of Akt at Ser473. The PI3K-dependent phosphorylation of Akt induces the movement of PDX-1 from the nucleus to the cytoplasm and regulates the proliferation of pancreatic β-cells.[147]17Naringin (4′,5,7-Trihydroxyflavanone 7-Rhamnoglucoside)Male adult Wistar rats (250–300 g)100 mg/kg p.o.It increases insulin gene expression and insulin secretion by upregulating the PDX-1 gene and protein expression.[148]18Small molecule kaempferolINS-1E cells0.1 μM, 1 μM, 10 μMIt protects islet cells through PDX-1/cAMP/PKA/CREB signaling pathway.[163]19ResveratrolαTC9 cells25 μMIt inhibits histone deacetylase and promotes insulin expression synthesis by increasing PDX-1 expression levels.[164]20Jin-tang-ning (JTN)8-week-old female KKAy mice and gender-matched C57BL/6J mice8 g JTN powder/kgIt upregulates expression levels of GCK and PDX-1.[165]21DA-12417-week-old male ICR mice and Sprague-Dawley (SD) rats100 mg/kg i.p.It can preserve pancreatic functions by suppressing ER stress and increasing PDX-1 expression.[142]22Acarbose8-week-old db/db mice and male -+/db mice9 g/kgIt prevents the nuclear export of PDX-1 and blocks the increase in methylated PDX-1 in T2DM mouse β-cells.[144]23LiraglutideRat RINm5F β-cell0.1 μmol/LIt can restore the expression of PDX-1 and upregulate mitophagy to restore mitochondrial function and ameliorate β-cell impairment.[143]24Exendin-43-week-old C57BL/6J mice10 μg/kgIt can improve T2DM progression by reversing global pancreatic histone H3K9 and H3K23 acetylation, H3K4 mono-methylation, and H3K9 di-methylation and also reverse the inhibitory state of PDX-1.[141]

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