The Pal elements in the upstream glucokinase promoter exhibit dyad symmetry and display cell-specific enhancer activity when multimerised

Moates, J. M.; Magnuson, Mark A.

doi:10.1007/s00125-004-1497-1

Cited by 9 publications

(7 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The Rfx3 binding sites correspond to two palindromic sequences (Pal-1 and Pal-2) that are essential for regulating β-cell activity of the neuroendocrine promoter in rodents and humans (34,35,39). Gel-retardation, footprint, methylation-interference, and cross-linking experiments have demonstrated that Pal-1 and Pal-2 are recognized by nuclear factors in β-cells (33–35,39). Until now, the identity of these factors remained unknown.…”

Section: Discussionmentioning

confidence: 99%

The Transcription Factor Rfx3 Regulates β-Cell Differentiation, Function, and Glucokinase Expression

et al. 2010

View full text Add to dashboard Cite

OBJECTIVEPancreatic islets of perinatal mice lacking the transcription factor Rfx3 exhibit a marked reduction in insulin-producing β-cells. The objective of this work was to unravel the cellular and molecular mechanisms underlying this deficiency.RESEARCH DESIGN AND METHODSImmunofluorescence studies and quantitative RT-PCR experiments were used to study the emergence of insulin-positive cells, the expression of transcription factors implicated in the differentiation of β-cells from endocrine progenitors, and the expression of mature β-cell markers during development in Rfx3−/− and pancreas-specific Rfx3-knockout mice. RNA interference experiments were performed to document the consequences of downregulating Rfx3 expression in Min6 β-cells. Quantitative chromatin immunoprecipitation (ChIP), ChIP sequencing, and bandshift experiments were used to identify Rfx3 target genes.RESULTSReduced development of insulin-positive cells in Rfx3−/− mice was not due to deficiencies in endocrine progenitors or β-lineage specification, but reflected the accumulation of insulin-positive β-cell precursors and defective β-cells exhibiting reduced insulin, Glut-2, and Gck expression. Similar incompletely differentiated β-cells developed in pancreas-specific Rfx3-deficient embryos. Defective β-cells lacking Glut-2 and Gck expression dominate in Rfx3-deficent adults, leading to glucose intolerance. Attenuated Glut-2 and glucokinase expression, and impaired glucose-stimulated insulin secretion, were also induced by RNA interference–mediated inhibition of Rfx3 expression in Min6 cells. Finally, Rfx3 was found to bind in Min6 cells and human islets to two well-known regulatory sequences, Pal-1 and Pal-2, in the neuroendocrine promoter of the glucokinase gene.CONCLUSIONSOur results show that Rfx3 is required for the differentiation and function of mature β-cells and regulates the β-cell promoter of the glucokinase gene.

show abstract

Section: Discussionmentioning

confidence: 99%

The Transcription Factor Rfx3 Regulates β-Cell Differentiation, Function, and Glucokinase Expression

et al. 2010

View full text Add to dashboard Cite

show abstract

“…Symmetry is a frequent feature of regulatory sequences, including box I of Tnt1 [14], an activator in the 5'UTR of Copia element [40] and the Pal elements in the β-glucokinase promoter of neuroendocrine pancreatic, gut and brain cells in humans and mice [41]. The position of the boxes in the LTRs and upstream of the ENV -gene does not seem random and they also form CpG islands that are by default found at the 5' side of genes regulating their expression [29].…”

Section: Discussionmentioning

confidence: 99%

Highly conserved motifs in non-coding regions of Sirevirus retrotransposons: the key for their pattern of distribution within and across plants?

et al. 2010

View full text Add to dashboard Cite

BackgroundRetrotransposons are key players in the evolution of eukaryotic genomes. Moreover, it is now known that some retrotransposon classes, like the abundant and plant-specific Sireviruses, have intriguingly distinctive host preferences. Yet, it is largely unknown if this bias is supported by different genome structures.ResultsWe performed sensitive comparative analysis of the genomes of a large set of Ty1/copia retrotransposons. We discovered that Sireviruses are unique among Pseudoviridae in that they constitute an ancient genus characterized by vastly divergent members, which however contain highly conserved motifs in key non-coding regions: multiple polypurine tract (PPT) copies cluster upstream of the 3' long terminal repeat (3'LTR), of which the terminal PPT tethers to a distinctive attachment site and is flanked by a precisely positioned inverted repeat. Their LTRs possess a novel type of repeated motif (RM) defined by its exceptionally high copy number, symmetry and core CGG-CCG signature. These RM boxes form CpG islands and lie a short distance upstream of a conserved promoter region thus hinting towards regulatory functions. Intriguingly, in the envelope-containing Sireviruses additional boxes cluster at the 5' vicinity of the envelope. The 5'LTR/internal domain junction and a polyC-rich integrase signal are also highly conserved domains of the Sirevirus genome.ConclusionsOur comparative analysis of retrotransposon genomes using advanced in silico methods highlighted the unique genome organization of Sireviruses. Their structure may dictate a life cycle with different regulation and transmission strategy compared to other Pseudoviridae, which may contribute towards their pattern of distribution within and across plants.

show abstract

“…Two major functional cis -acting elements were delineated in this promoter fragment [ 43 ]. One element bound proteins which did not match known transcription factors [ 44 ], whereas the other element was identified as a binding site for Beta2/NeuroD, a basic helix-loophelix zipper (bHLHz) transcriptional activator important in the ontogeny of the endocrine pancreas [ 45 ]. Another key transcription factor of early pancreas development, Pdx-1, was proposed to activate the neuroendocrine GCK promoter [ 46 ], but this notion was subsequently dispelled [ 47 ].…”

Section: Regulation Of Glucokinase Gene Expressionmentioning

confidence: 99%

Molecular Physiology of Mammalian Glucokinase

Iynedjian

2008

Cell. Mol. Life Sci.

322

294

View full text Add to dashboard Cite

Abstract. The glucokinase (GCK) gene was one of the first candidate genes to be identified as a human "diabetes gene". Subsequently, important advances were made in understanding the impact of GCK in the regulation of glucose metabolism. Structure elucidation by crystallography provided insight into the kinetic properties of GCK. Protein interaction partners of GCK were discovered. Gene expression studies revealed new facets of the tissue distribution of GCK, including in the brain, and its regulation by insulin in the liver. Metabolic control analysis coupled to gene overexpression and knockout experiments highlighted the unique impact of GCK as a regulator of glucose metabolism. Human GCK mutants were studied biochemically to understand disease mechanisms. Drug development programs identified small molecule activators of GCK as potential antidiabetics. These advances are summarized here, with the aim of offering an integrated view of the role of GCK in the molecular physiology and medicine of glucose homeostasis.

show abstract

The Pal elements in the upstream glucokinase promoter exhibit dyad symmetry and display cell-specific enhancer activity when multimerised

Cited by 9 publications

References 38 publications

The Transcription Factor Rfx3 Regulates β-Cell Differentiation, Function, and Glucokinase Expression

The Transcription Factor Rfx3 Regulates β-Cell Differentiation, Function, and Glucokinase Expression

Highly conserved motifs in non-coding regions of Sirevirus retrotransposons: the key for their pattern of distribution within and across plants?

Molecular Physiology of Mammalian Glucokinase

Contact Info

Product

Resources

About