The subcellular localization of the ChoRE-binding protein, encoded by the Williams–Beuren syndrome critical region gene 14, is regulated by 14-3-3

Merla, Giuseppe; Howald, Cédric; Antonarakis, Stylianos E.; Reymond, Alexandre

doi:10.1093/hmg/ddh163

Cited by 65 publications

(72 citation statements)

References 61 publications

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“…Cytoplasmic localization of ChREBP. Our results corroborated the finding of Merla et al (27), i.e., the predominant cytoplasmic localization of ChREBP (Fig. 5).…”

Section: Discussionsupporting

confidence: 93%

“…This indicates that the transactivation activity of ChREBP itself is the most likely target of glucose regulation. Although it was reported previously that the LID region has a documented repression activity (14), this activity was later attributed to its cytoplasmic retention effect, rather than corepressor recruitment (27). Consistently, we found that LID cannot confer glucose responsiveness to GAL4-LID-VP16 as we would expect if glucose responsiveness is due to reversible recruitment of core-pressors by LID (Fig.…”

Section: Discussionsupporting

confidence: 88%

“…5). As if one were not enough, evolution imposes two separate cytoplasmic localization signals along with a 14-3-3 binding site to keep Mondo proteins away from nucleus (15,27). Although it is counterintuitive that a functional transcription factor should be mainly cytoplasmic, this distribution pattern may be functionally important.…”

Section: Discussionmentioning

confidence: 99%

“…It was reported previously that the GSM region harbors a strong cytoplasmic localization signal that retains WBSCR14/ChREBP and MondoA in the cytoplasm (15,27). To determine whether glucose can drive ChREBP into the nucleus in 832/13 cells, we generated GFP fusion proteins with wild type and select mutants of ChREBP and examined their subcellular localization under different glucose concentrations.…”

mentioning

confidence: 99%

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Glucose-Dependent Transcriptional Regulation by an Evolutionarily Conserved Glucose-Sensing Module

et al. 2006

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We report here a novel mechanism for glucose-mediated activation of carbohydrate response element binding protein (ChREBP), a basic helix-loop-helix/leucine zipper (bHLH/ZIP) transcription factor of Mondo family that binds to carbohydrate response element in the promoter of some glucose-regulated genes and activates their expression upon glucose stimulation. Structure-function analysis of ChREBP in a highly glucose-sensitive system using GAL4-ChREBP fusion constructs revealed a glucose-sensing module (GSM) that mediates glucose responsiveness of ChREBP. GSM is conserved among Mondo family members; MondoA, a mammalian paralog of unknown function, and the GSM region of a Drosophila homolog were also found to be glucose responsive. GSM is composed of a low-glucose inhibitory domain (LID) and a glucose-response activation conserved element (GRACE). We have identified a new mechanism accounting for glucose responsiveness of ChREBP that involves specific inhibition of the transactivation activity of GRACE by LID under low glucose concentration and reversal of this inhibition by glucose in an orientation-sensitive manner. The intramolecular inhibition and its release by glucose is a regulatory mechanism that is independent of changes of subcellular localization or DNA binding activity, events that also appear to be involved in glucose responsiveness. This evolutionally conserved mechanism may play an essential role in glucose-responsive gene regulation.

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“…Cytoplasmic localization of ChREBP. Our results corroborated the finding of Merla et al (27), i.e., the predominant cytoplasmic localization of ChREBP (Fig. 5).…”

Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Glucose-Dependent Transcriptional Regulation by an Evolutionarily Conserved Glucose-Sensing Module

et al. 2006

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“…It contains several functional domains including two nuclear export signal sites located at residues 5-15 and 86-95 (Merla et al 2004, Fukasawa et al 2010, a bipartite nuclear localisation signal site located at residues 158-190 (Ge et al 2011), a DNA-binding bHLH/Zip domain and proline-rich regions including multiple phosphorylation sites (Cairo et al 2001, Yamashita et al 2001. The N-terminal region of ChREBP (amino acids 1-251) interacts directly with a dimeric form of the 14-3-3 protein (Li et al 2006, Sakiyama et al 2008 and is responsible for sub-cellular localisation, while the C-terminal region of ChREBP forms a complex MLX to bind DNA (Cairo et al 2001, Stoeckman et al 2004).…”

Section: Molecular Structurementioning

confidence: 99%

Roles of Ca2+ ions in the control of ChREBP nuclear translocation

Leclerc

Rutter²,

Meur³

et al. 2012

Journal of Endocrinology

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Carbohydrate-responsive element binding protein (ChREBP (MLXIPL)) is emerging as an important mediator of glucotoxity both in the liver and in the pancreatic b-cells. Although the regulation of its nuclear translocation and transcriptional activation by glucose has been the subject of intensive research, it is still not fully understood. We have recently uncovered a novel mechanism in the excitable pancreatic b-cell where ChREBP interacts with sorcin, a penta-EF-hand Ca -sorcin element of ChREBP activation also exists in non-excitable cells is discussed.

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Molecular Genetics of Williams–Beuren Syndrome

Merla

Micale

Fusco

et al. 2012

Encyclopedia of Life Sciences

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The Williams–Beuren syndrome is a rare genomic disorder caused by a hemizygous microdeletion of approximately 30 genes at 7q11.23 occurring by nonallelic homologous recombination between low copy repeats flanking that region. The 7q11.23 region has been also found duplicated, triplicated and inverted in patients with different and, in some instances, reciprocal phenotypes. Complementary strategies including mouse models, functional and biochemical studies have been pursued in the recent years to delineate the individual and/or combined contribution of hemizygous genes to the wide spectrum of phenotypes that characterises this syndrome. Haploinsufficiency of several of these genes has been reported to account for parts of the overall phenotypes, suggesting their sensitivity to gene dosage. Notably, MLXIPL , GTF2IRD1 and GTF2I hemizygous genes act as transcription factors, therefore is likely that their haploinsufficiency is responsible for some of clinical features by regulating gene expression of a wide number of target genes. Key Concepts: Williams–Beuren syndrome is a genomic disorder characterised by a unique cognitive profile and it involves approximately 30 hemizygous genes at 7q11.23. The 7q11.23 Williams–Beuren syndrome region has been found deleted, duplicated, triplicated and inverted in patients with different phenotypes. Patients with atypical deletions and mouse models have provided insights about the genotype–phenotype correlations. Haploinsufficiency of the Williams–Beuren syndrome genes is correlated with the clinical signs. BAZ1B has been linked to cardiac, craniofacial and hypercalcemia defects; hemizygosity of MLXIPL could be related to the diabetic phenotype of Williams–Beuren syndrome patients through regulation of glucose metabolism. The GTF2IRD1 transcription factor modulates genes involved in tissue development and differentiation and is a strong candidate for the craniofacial and neurobehavioral features.

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The subcellular localization of the ChoRE-binding protein, encoded by the Williams–Beuren syndrome critical region gene 14, is regulated by 14-3-3

Cited by 65 publications

References 61 publications

Glucose-Dependent Transcriptional Regulation by an Evolutionarily Conserved Glucose-Sensing Module

Glucose-Dependent Transcriptional Regulation by an Evolutionarily Conserved Glucose-Sensing Module

Roles of Ca2+ ions in the control of ChREBP nuclear translocation

Molecular Genetics of Williams–Beuren Syndrome

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