PDX-1 Expression Is Associated with Islet Proliferation In Vitro and In Vivo

Feanny, Mark A.; Fagan, Shawn P.; Ballian, Nikiforos; Liu, Shi-He; Li, Zhijun; Wang, Xiaoping; Fisher, William E.; Brunicardi, F. Charles; Belaguli, Narasimhaswamy S.

doi:10.1016/j.jss.2007.04.018

Cited by 27 publications

(21 citation statements)

References 52 publications

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“…These findings are consistent with the fact that SSTR5 mediates the inhibitory effect of somatostatin on insulin secretion (Fagan et al, 1998; Tirone et al, 2003). A SSTR5 knockdown-induced increase of PDX-1 expression in mouse insulinoma MIN6 cells is accompanied by elevated expression of cyclin E and cdk4 and decreased expression of p21, p27, and p53, supporting previous studies showing that SSTR5 inhibits cell proliferation (Fagan et al, 1998; Feanny et al, 2008) and promotes apoptosis (Qiu et al, 2006). This also is consistent with a previous study showing that SSTR5 contributes to the induction of cyclin-dependent kinase inhibitor p27 (Grant et al, 2008); and (3) genetic ablation of SSTR5 results in increased expression of PDX-1, which is accompanied by increased expression of insulin and proliferating cell nuclear antigen (PCNA) in sstr5 −/− islets.…”

Section: Negative Regulation Of Pdx-1 By Sstr5supporting

confidence: 79%

“…Also consistent is the finding that all three SSTR5 knockout mice (general SSTR5 −/− , β cell-specific SSTR5 −/− and SSTR1/5 −/− , SSTR1 and SSTR5 double knockout) develop islet hyperplasia, increased numbers of islets and islet neogenesis compared with littermate wild type controls (Wang et al, 2004, 2005a,b). Given the essential role of PDX-1 in insulin expression (Ashizawa et al, 2004; Kaneto et al, 2007) and cell proliferation (Feanny et al, 2008), these studies support a new concept that SSTR5 may mediate the inhibitory effect of somatostatin on insulin expression and secretion and cell proliferation through a mechanism involving inhibiting PDX-1 expression.…”

Section: Negative Regulation Of Pdx-1 By Sstr5mentioning

confidence: 74%

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Down-regulation of pancreatic and duodenal homeobox-1 by somatostatin receptor subtype 5: a novel mechanism for inhibition of cellular proliferation and insulin secretion by somatostatin

et al. 2014

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Somatostatin (SST) is a regulatory peptide and acts as an endogenous inhibitory regulator of the secretory and proliferative responses of target cells. SST’s actions are mediated by a family of seven transmembrane domain G protein-coupled receptors that comprise five distinct subtypes (SSTR1-5). SSTR5 is one of the major SSTRs in the islets of Langerhans. Homeodomain-containing transcription factor pancreatic and duodenal homeobox-1 (PDX-1) is essential for pancreatic development, β cell differentiation, maintenance of normal β cell functions in adults and tumorigenesis. Recent studies show that SSTR5 acts as a negative regulator for PDX-1 expression and that SSTR5 mediates somatostatin’s inhibitory effect on cell proliferation and insulin expression/excretion through down-regulating PDX-1 expression. SSTR5 exerts its inhibitory effect on PDX-1 expression at both the transcriptional level by down-regulating PDX-1 mRNA and the post-translational level by enhancing PDX-1 ubiquitination. Identification of PDX-1 as a transcriptional target for SSTR5 may help in guiding the choice of therapeutic cancer treatments.

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Section: Negative Regulation Of Pdx-1 By Sstr5supporting

confidence: 79%

Section: Negative Regulation Of Pdx-1 By Sstr5mentioning

confidence: 74%

Down-regulation of pancreatic and duodenal homeobox-1 by somatostatin receptor subtype 5: a novel mechanism for inhibition of cellular proliferation and insulin secretion by somatostatin

et al. 2014

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“…PDX1 is essential for differentiation and maturation of pancreatic precursor cells towards β cells in the developing pancreas, and it is also the key regulator of insulin gene expression for postnatal β cell functions (1,2). During mouse early embryonic development, PDX1 expression can be firstly detected at embryonic day 8.5 in the dorsal and ventral buds that form pancreas; while in the adult stage, PDX1 is mainly expressed and functions in the β cells of the islet.…”

Section: Pdx1 and Pdx1 Involved Diseasesmentioning

confidence: 99%

“…It is known that PDX1 maintains mature β cell function and glucose metabolism through regulating the expression of multiple key endocrine β-cell-specific genes including insulin, glucokinase, islet amyloid polypeptide and the glucose transporter type 2. Deletion or homozygous inactive mutations in PDX1 is lethal in mice due to whole pancreatic agenesis (2,3). Conditional knockout of PDX1 gene in β cells leads to overt diabetes, whereas knockingdown of PDX1 expression results in decreased insulin secretion in mice (4).…”

Section: Pdx1 and Pdx1 Involved Diseasesmentioning

confidence: 99%

PDX1 associated therapy in translational medicine

Yu¹,

Liu²,

Sanchez³

et al. 2016

Ann. Transl. Med.

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Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extremely poor prognosis and a low median survival due to lack of the early and reliable detection and effective therapeutic options, despite improvements observed for many other cancers in last decade. Pancreatic and duodenal homeobox 1 (PDX1), which is a homeodomain-containing transcription factor and a key regulator for insulin gene expression, β cell maturation and proper β cell function maintenance in the pancreas. Our previous studies revealed that PDX1 promotes tumorigenesis and it is a promising therapeutic target for PDAC. For translational purposes, we developed three therapeutic platforms utilizing RNA interference (RNAi), gene therapy and small inhibitory drug targeting PDX1, and further validated them in PDAC preclinical models both in vitro and in vivo. These PDX1 targeted therapies significantly inhibited PDX1 expression in PDAC cells, ablated PDX1-expressing human PDAC xenograft tumor growth, and prolonged survival in the PDAC mouse models. The data from these preclinical studies proved the translational potentials of PDX1 targeted therapies in PDAC and suggest that the strategy of developing PDX1 targeted therapies would permit a rapid bench-to-bedside translation of other relevant gene therapies, which would eventually benefit the patients suffering from this deadly disease.

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“…Moreover, Pdx-1 deficiency leads to increased apoptosis, autophagy, and susceptibility to endoplasmic reticulum (ER) stress (14)(15)(16), suggesting that Pdx-1 is essential for ␤-cell survival. Pdx-1 expression has been associated with proliferation or increased ␤-cell mass in remnant islets (24) and in pancreatic ductal cells after partial (90%) pancreatectomy (25). While Pdx-1 transgenic mice have a 2-fold increase of 5-bromo-2-deoxyuridine (BrdU) labeling in ␤ cells compared to wild-type mice (22), the impact of acute expression of Pdx-1 on proliferation in isolated islets has not been studied, and the mechanisms by which Pdx-1 might induce proliferation are unknown.…”

mentioning

confidence: 99%

Pdx-1 Activates Islet α- and β-Cell Proliferation via a Mechanism Regulated by Transient Receptor Potential Cation Channels 3 and 6 and Extracellular Signal-Regulated Kinases 1 and 2

Hayes

Moss

Schisler

et al. 2013

Molecular and Cellular Biology

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The homeodomain transcription factor Pdx-1 has important roles in pancreatic development and ␤-cell function and survival. In the present study, we demonstrate that adenovirus-mediated overexpression of Pdx-1 in rat or human islets also stimulates cell replication. Moreover, cooverexpression of Pdx-1 with another homeodomain transcription factor, Nkx6.1, has an additive effect on proliferation compared to either factor alone, implying discrete activating mechanisms. Consistent with this, Nkx6.1 stimulates mainly ␤-cell proliferation, whereas Pdx-1 stimulates both ␣-and ␤-cell proliferation. Furthermore, cyclins D1/D2 are upregulated by Pdx-1 but not by Nkx6.1, and inhibition of cdk4 blocks Pdx-1-stimulated but not Nkx6.1-stimulated islet cell proliferation. Genes regulated by Pdx-1 but not Nkx6.1 were identified by microarray analysis. Two members of the transient receptor potential cation (TRPC) channel family, TRPC3 and TRPC6, are upregulated by Pdx-1 overexpression, and small interfering RNA (siRNA)-mediated knockdown of TRPC3/6 or TRPC6 alone inhibits Pdx-1-induced but not Nkx6.1-induced islet cell proliferation. Pdx-1 also stimulates extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation, an effect partially blocked by knockdown of TRPC3/6, and blockade of ERK1/2 activation with a MEK1/2 inhibitor partially impairs Pdx-1-stimulated proliferation. These studies define a pathway by which overexpression of Pdx-1 activates islet cell proliferation that is distinct from and additive to a pathway activated by Nkx6.1.

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PDX-1 Expression Is Associated with Islet Proliferation In Vitro and In Vivo

Cited by 27 publications

References 52 publications

Down-regulation of pancreatic and duodenal homeobox-1 by somatostatin receptor subtype 5: a novel mechanism for inhibition of cellular proliferation and insulin secretion by somatostatin

Down-regulation of pancreatic and duodenal homeobox-1 by somatostatin receptor subtype 5: a novel mechanism for inhibition of cellular proliferation and insulin secretion by somatostatin

PDX1 associated therapy in translational medicine

Pdx-1 Activates Islet α- and β-Cell Proliferation via a Mechanism Regulated by Transient Receptor Potential Cation Channels 3 and 6 and Extracellular Signal-Regulated Kinases 1 and 2

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