Ca2+-activated Nucleotidase 1, a Novel Target Gene for the Transcriptional Repressor DREAM (Downstream Regulatory Element Antagonist Modulator), Is Involved in Protein Folding and Degradation

Calì, Tito; Fedrizzi, Laura; Ottolini, Denis; Gómez‐Villafuertes, Rosa; Mellström, Britt; Naranjo, José R.; Carafoli, Ernesto; Brini, Marisa

doi:10.1074/jbc.m111.304733

Cited by 15 publications

(14 citation statements)

References 60 publications

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“…Real-time qPCR analysis confirmed the reduced level of Mid1 mRNA in the cerebellum of adult transgenic mice as well as in the hippocampus (Figure 2A), areas with significant expression of daDREAM (Figure 2B). As reported for other DREAM target genes like prodynorphin in the hippocampus (Cheng et al, 2002) or CANT1 in the cerebellum (Cali et al, 2012), probably due to functional compensation by other members of the KChIP family, no change in the expression of Mid1 was observed in cerebellum or hippocampus from DREAM knockout mice (Figure 2C). Western blot analysis of cerebellum and hippocampus from daDREAM mice confirmed the reduced levels of Mid1 protein with respect to wild type mice (Figure 2D).…”

Section: Resultssupporting

confidence: 77%

Reduced Mid1 Expression and Delayed Neuromotor Development in daDREAM Transgenic Mice

Dierssen¹,

Fedrizzi²,

Gómez‐Villafuertes³

et al. 2012

Front. Mol. Neurosci.

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Downstream regulatory element antagonist modulator (DREAM) is a Ca2+-binding protein that binds DNA and represses transcription in a Ca2+-dependent manner. Previous work has shown a role for DREAM in cerebellar function regulating the expression of the sodium/calcium exchanger 3 (NCX3) in cerebellar granular neurons to control Ca2+ homeostasis and survival of these neurons. To achieve a global view of the genes regulated by DREAM in the cerebellum, we performed a genome-wide analysis in transgenic cerebellum expressing a Ca2+-insensitive/CREB-independent dominant active mutant DREAM (daDREAM). Here we show that DREAM regulates the expression of the midline 1 (Mid1) gene early after birth. As a consequence, daDREAM mice exhibit a significant shortening of the rostro-caudal axis of the cerebellum and a delay in neuromotor development early after birth. Our results indicate a role for DREAM in cerebellar function.

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Section: Resultssupporting

confidence: 77%

Reduced Mid1 Expression and Delayed Neuromotor Development in daDREAM Transgenic Mice

Dierssen¹,

Fedrizzi²,

Gómez‐Villafuertes³

et al. 2012

Front. Mol. Neurosci.

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“…Thus, unlike apyrases found in the blood-feeding arthropods, the substrate preference and subcellular localization of the enzyme suggest very different functions in mammals. In fact, CANT1 is likely involved in the intracellular glycosylation reactions and, in addiction, in protein quality control and folding as demonstrated in neuroblastoma cell lines [14]. Moreover, since uridine nucleotides as well as UDP-sugars are also recognized as extracellular signaling molecules, the presence of the soluble secreted form of CANT1 suggests that the enzyme may also modulate cellular responses to extracellular UDP via specific pyrimidinergic receptors (P2Y family) [15].…”

Section: Introductionmentioning

confidence: 99%

Calcium activated nucleotidase 1 (CANT1) is critical for glycosaminoglycan biosynthesis in cartilage and endochondral ossification

et al. 2019

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Desbuquois dysplasia type 1 (DBQD1) is a chondrodysplasia caused by mutations in CANT1 gene encoding an ER/Golgi calcium activated nucleotidase 1 that hydrolyses UDP. Here, using Cant1 knock-in and knock-out mice recapitulating DBQD1 phenotype, we report that CANT1 plays a crucial role in cartilage proteoglycan synthesis and in endochondral ossification. Specifically, the glycosaminoglycan synthesis was decreased in chondrocytes from Cant1 knock-out mice and their hydrodynamic size was reduced, whilst the sulfation was increased and the overall proteoglycan secretion was delayed. Interestingly, knock-out chondrocytes had dilated ER cisternae suggesting delayed protein secretion and cellular stress; however, no canonical ER stress response was detected using microarray analysis, Xbp1 splicing and protein levels of BiP and ATF4. The observed proteoglycan defects caused deregulated chondrocyte proliferation and maturation in the growth plate resulting in the reduced skeletal growth. In conclusion, the pathogenic mechanism of DBQD1 comprises deregulated chondrocyte performance due to defective intracellular proteoglycan synthesis and altered proteoglycan properties in the extracellular matrix.

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“…In DREAM knockout mouse we found: i) no differences in the placental GCM1 expression levels, ii) no changes in the placental development (weight, morphology), and iii) no changes in embryonic weights (Figure S3), possibly due to gene compensation by the other members of the DREAM/KChIP family of proteins [34], [38]. Conversely, given our findings of over-expression of DREAM in sPE placentas, we focused on a DREAM over-expressing mouse model [23] [28], hypothesizing that this strain will display pre-eclamptic-like signs.…”

Section: Discussionmentioning

confidence: 78%

DREAM Mediated Regulation of GCM1 in the Human Placental Trophoblast

Baczyk

Kibschull

Mellström³

et al. 2013

PLoS ONE

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The trophoblast transcription factor glial cell missing-1 (GCM1) regulates differentiation of placental cytotrophoblasts into the syncytiotrophoblast layer in contact with maternal blood. Reduced placental expression of GCM1 and abnormal syncytiotrophoblast structure are features of hypertensive disorder of pregnancy – preeclampsia. In-silico techniques identified the calcium-regulated transcriptional repressor – DREAM (Downstream Regulatory Element Antagonist Modulator) - as a candidate for GCM1 gene expression. Our objective was to determine if DREAM represses GCM1 regulated syncytiotrophoblast formation. EMSA and ChIP assays revealed a direct interaction between DREAM and the GCM1 promoter. siRNA-mediated DREAM silencing in cell culture and placental explant models significantly up-regulated GCM1 expression and reduced cytotrophoblast proliferation. DREAM calcium dependency was verified using ionomycin. Furthermore, the increased DREAM protein expression in preeclamptic placental villi was predominantly nuclear, coinciding with an overall increase in sumolylated DREAM and correlating inversely with GCM1 levels. In conclusion, our data reveal a calcium-regulated pathway whereby GCM1-directed villous trophoblast differentiation is repressed by DREAM. This pathway may be relevant to disease prevention via calcium-supplementation.

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Ca2+-activated Nucleotidase 1, a Novel Target Gene for the Transcriptional Repressor DREAM (Downstream Regulatory Element Antagonist Modulator), Is Involved in Protein Folding and Degradation

Cited by 15 publications

References 60 publications

Reduced Mid1 Expression and Delayed Neuromotor Development in daDREAM Transgenic Mice

Reduced Mid1 Expression and Delayed Neuromotor Development in daDREAM Transgenic Mice

Calcium activated nucleotidase 1 (CANT1) is critical for glycosaminoglycan biosynthesis in cartilage and endochondral ossification

DREAM Mediated Regulation of GCM1 in the Human Placental Trophoblast

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