Pax6 and Pdx1 form a functional complex on the rat somatostatin gene upstream enhancer

Andersen, Frank G.; Jensen, Jan; Heller, R. Scott; Petersen, Helle V.; Larsson, Lars; Madsen, Ole; Serup, Palle

doi:10.1016/s0014-5793(99)00144-1

Cited by 54 publications

(35 citation statements)

References 47 publications

(58 reference statements)

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“…2C), where expression of Pdx1, Nkx2.2, Nkx6.1, Pax4, and Pax6 by Aire Ϫ/Ϫ MTEC was reduced to ϳ5% of WT levels. It is noteworthy that severe reductions in Pdx1 expression by the Aire-deficient MTEC population was mirrored by severe reductions in the expression of three endocrine structural genes, Ins, Sst, and Gip, that are directly regulated by Pdx1 and whose promoters are binding targets for Pdx1 (32)(33)(34). These results demonstrate that the genes affected by Aire deficiency in MTEC extend beyond structural products of peripheral lineages to include the regulatory elements that control expression of these genes in peripheral tissues.…”

Section: Aire Deficiency Leads To Severe Reductions In the Pancreaticmentioning

confidence: 77%

Aire-Dependent Alterations in Medullary Thymic Epithelium Indicate a Role for Aire in Thymic Epithelial Differentiation

Gillard¹,

Dooley²,

Erickson³

et al. 2007

The Journal of Immunology

114

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The prevalent view of thymic epithelial differentiation and Aire activity holds that Aire functions in terminally differentiated medullary thymic epithelial cells (MTECs) to derepress the expression of structural tissue-restricted Ags, including pancreatic endocrine hormones. An alternative view of these processes has proposed that Aire functions to regulate the differentiation of immature thymic epithelial cells, thereby affecting tissue-restricted Ag expression and negative selection. In this study, we demonstrate that Aire impacts several aspects of murine MTECs and provide support for this second model. Expression of transcription factors associated with developmental plasticity of progenitor cells, Nanog, Oct4, and Sox2, by MTECs was Aire dependent. Similarly, the transcription factors that regulate pancreatic development and the expression of pancreatic hormones are also expressed by wild-type MTECs in an Aire-dependent manner. The altered transcriptional profiles in Aire-deficient MTECs were accompanied by changes in the organization and composition of the medullary epithelial compartment, including a reduction in the medullary compartment defined by keratin (K) 14 expression, altered patterns of K5 and K8 expression, and more prominent epithelial cysts. These findings implicate Aire in the regulation of MTEC differentiation and the organization of the medullary thymic compartment and are compatible with a role for Aire in thymic epithelium differentiation.

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Section: Aire Deficiency Leads To Severe Reductions In the Pancreaticmentioning

confidence: 77%

Aire-Dependent Alterations in Medullary Thymic Epithelium Indicate a Role for Aire in Thymic Epithelial Differentiation

Gillard¹,

Dooley²,

Erickson³

et al. 2007

The Journal of Immunology

114

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“…Three transcriptional factors, CREB, pancreatic and duodenal homeobox 1 (PDX1) and PAX6, have been identified as binding to the somatostatin promoter region between −109 and 100 [20][21][22] (Fig. 4c).…”

Section: /β2armentioning

confidence: 99%

A stress response pathway in mice upregulates somatostatin level and transcription in pancreatic delta cells through Gs and β-arrestin 1

Wang

Dong

et al. 2014

Diabetologia

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Aims/hypothesis Somatostatin secretion from islet delta cells plays an important role in regulating islet function and is tightly controlled by environmental changes. Activation of the adrenergic system promoted somatostatin secretion from islet delta cells; however, the role of the adrenergic system in regulating somatostatin content and transcription has not been defined. An imbalance between the somatostatin content and its secretion may cause dysfunctions in the islet delta cells. We have investigated the role of the adrenergic system in the modulation of somatostatin content and transcription in pancreatic delta cells and the detailed underlying mechanisms of this regulation. Methods The stress hormone adrenaline (epinephrine), specific adrenergic agonists or specific adrenergic antagonists were applied to islets from either wild-type or specific adrenergic receptor knockout mice and pancreatic delta cell lines to investigate their effects on somatostatin content and transcription. The GloSensor assay, quantitative real-time PCR, western blots and the dual luciferase assay were used to monitor the cAMP level, somatostatin expression, activations of kinases and transcriptional factors. Arrb1 knockout mice, specific Creb or Pax6 mutations and specific kinase inhibitors were used to dissect the signalling pathway. Results Adrenaline and isoprenaline increased somatostatin content and transcription through the activation of β1-/β2-adrenergic receptors (β1-/β2ARs). The somatostatin content in β1AR−/− (Adrb1/Adrb2 knockout) mice was 50% lower than in β1AR +/+ /β2AR +/+ mice. Two parallel signalling pathways, Gs-cAMP-protein kinase A (PKA)-cAMP response element binding protein (CREB) and β-arrestin 1-extracellular signal-related kinase (ERK)-paired box protein 6 (PAX6), cooperatively regulated isoprenaline-induced somatostatin transcription. Conclusions/interpretation A stress pathway increased somatostatin content and transcription through β-adrenergic agonism. β-Arrestin1, ERK and PAX6 are important pancreatic delta cell regulators in addition to cAMP, PKA and CREB. Dysfunction of β-adrenergic agonism may impair pancreatic delta cell function.

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“…A point mutation in the A-element that abolishes both PDX-1 and PBX binding has been shown to be unable to reduce the promoter activity (57). In contrast, a point mutation that selectively eliminates PDX-1 binding to a proximal B-element reduces the promoter activity.…”

Section: Somatostatinmentioning

confidence: 99%

“…Pax6 binding is essential for the promoter activity and a stop codon mutation in the A-element has been shown to reduce both Pax6 binding and somatostatin gene transcription. Andersen et al (57) proposed that the b/d-cellspecific activity of the SMS-UE is achieved through simultaneous binding of PDX-1 and Pax6 to the Band C-elements respectively. It has been demonstrated that PDX-1 forms a heterodimeric complex with PBX, the mammalian homologue of the Drosophila extradenticle.…”

Section: Somatostatinmentioning

confidence: 99%

“…The antp-type hexapeptide present in the sequence of PDX-1 mediates its heterodimerization with the DNAbinding protein termed PBX on a regulatory element of the somatostatin promoter (16,17). PBX is an ubiquitous homeodomain protein that by forming a complex with PDX-1 and MRG1 (another homeodomain protein) regulates the expansion of ductal, endocrine, and acinar lineages during development.…”

Section: Introductionmentioning

confidence: 99%

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Pancreas duodenum homeobox-1 regulates pancreas development during embryogenesis and islet cell function in adulthood

Hui

Perfetti²

2002

European Journal of Endocrinology

121

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Pancreas duodenum homeobox-1 (PDX-1) (also known as insulin promoter factor-1, islet/duodenum homeobox-1, somatostatin transactivating factor-1, insulin upstream factor-1 and glucose-sensitive factor) is a transcription factor encoded by a Hox-like homeodomain gene. In humans and other animal species, the embryonic development of the pancreas requires PDX-1, as demonstrated by the identification of an individual with pancreatic agenesis resulting from a mutation that impaired the transcription of a functionally active PDX-1 protein. In adult subjects, PDX-1 is essential for normal pancreatic islet function as suggested by its regulatory action on the expression of a number of pancreatic genes, including insulin, somatostatin, islet amyloid polypeptide, the glucose transporter type 2 and glucokinase. Furthermore, heterozygous mutations of PDX-1 have been linked to a type of autosomal dominant form of diabetes mellitus known as maturity onset diabetes of the young type 4. The dual action of PDX-1, as a differentiation factor during embryogenesis and as a regulator of islet cell physiology in mature islet cells, underscores the unique role of PDX-1 in health and disease of the human endocrine pancreas.

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Pax6 and Pdx1 form a functional complex on the rat somatostatin gene upstream enhancer

Cited by 54 publications

References 47 publications

Aire-Dependent Alterations in Medullary Thymic Epithelium Indicate a Role for Aire in Thymic Epithelial Differentiation

Aire-Dependent Alterations in Medullary Thymic Epithelium Indicate a Role for Aire in Thymic Epithelial Differentiation

A stress response pathway in mice upregulates somatostatin level and transcription in pancreatic delta cells through Gs and β-arrestin 1

Pancreas duodenum homeobox-1 regulates pancreas development during embryogenesis and islet cell function in adulthood

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