Calcineurin Regulates Nuclear Factor I Dephosphorylation and Activity in Malignant Glioma Cell Lines

Brun, Miranda; Glubrecht, Darryl; Baksh, Shairaz; Godbout, Roseline

doi:10.1074/jbc.m113.455832

Cited by 17 publications

(18 citation statements)

References 81 publications

(111 reference statements)

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“…The B1 regulatory subunit of calcineurin, Ppp3r1 , was a gCIS in our screen and the catalytic subunit Ppp3ca was insertionally mutated in two tumors as well ( Table S2 ). Recently, the catalytic subunit of calcineurin was shown by IHC to be expressed in regions of high infiltration/migration in human GBMs [45] , however microarray data indicate that PPP3R1 ( Table 4 ) and PPP3CA (not shown) are under-expressed in human GBM compared to normal brain. Therefore further experiments will be necessary to characterize the contribution of calcineurin to gliomagenesis.…”

Section: Discussionmentioning

confidence: 97%

Sleeping Beauty Mouse Models Identify Candidate Genes Involved in Gliomagenesis

et al. 2014

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Genomic studies of human high-grade gliomas have discovered known and candidate tumor drivers. Studies in both cell culture and mouse models have complemented these approaches and have identified additional genes and processes important for gliomagenesis. Previously, we found that mobilization of Sleeping Beauty transposons in mice ubiquitously throughout the body from the Rosa26 locus led to gliomagenesis with low penetrance. Here we report the characterization of mice in which transposons are mobilized in the Glial Fibrillary Acidic Protein (GFAP) compartment. Glioma formation in these mice did not occur on an otherwise wild-type genetic background, but rare gliomas were observed when mobilization occurred in a p19Arf heterozygous background. Through cloning insertions from additional gliomas generated by transposon mobilization in the Rosa26 compartment, several candidate glioma genes were identified. Comparisons to genetic, epigenetic and mRNA expression data from human gliomas implicates several of these genes as tumor suppressor genes and oncogenes in human glioblastoma.

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Section: Discussionmentioning

confidence: 97%

Sleeping Beauty Mouse Models Identify Candidate Genes Involved in Gliomagenesis

et al. 2014

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“…In MG, NFI regulates FABP7, the expression of which coincides with increased tumor cell migration, tumor infiltration, and worse clinical prognosis (10,12,13,44). In the context of MG cells, NFI transcriptional activity is regulated by its phosphorylation state (45), with dephosphorylation of NFI mediated by the calcineurin phosphatase, a well-known target of calpain (21,46,47).…”

Section: Discussionmentioning

confidence: 99%

“…To examine the importance of NFI phosphorylation state for calpastatin subcellular localization, we treated U251 MG cells with 1 M cyclosporin A (CSA), an inhibitor of calcineurin that promotes NFI hyperphosphorylation (21). CSA-treated U251 MG cells showed increased levels of hyperphosphorylated NFI (indicated by the asterisks) (Fig.…”

Section: Cast Gene Regulation In Glioblastoma Cellsmentioning

confidence: 99%

“…NFI is differentially phosphorylated in MG cells, with the hypophosphorylated form of NFI correlating with FABP7 and GFAP expression (15). Dephosphorylation of NFI is mediated by calcineurin, a calcium-dependent serine/threonine phosphatase (21). Calcineurin, in turn, is cleaved and activated by calpain, a family of calcium-dependent nonlysosomal cysteine proteases (22,23).…”

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confidence: 99%

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Effects of nuclear factor I phosphorylation on calpastatin (CAST) gene variant expression and subcellular distribution in malignant glioma cells

Burchett

Brun

Monckton

et al. 2019

Journal of Biological Chemistry

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Edited by Xiao-Fan Wang Malignant glioma (MG) is the most lethal primary brain tumor. In addition to having inherent resistance to radiation treatment and chemotherapy, MG cells are highly infiltrative, rendering focal therapies ineffective. Genes involved in MG cell migration and glial cell differentiation are up-regulated by hypophosphorylated nuclear factor I (NFI), which is dephosphorylated by the phosphatase calcineurin in MG cells. Calcineurin is cleaved and thereby activated by calpain proteases, which are, in turn, inhibited by calpastatin (CAST). Here, we show that the CAST gene is a target of NFI and has NFI-binding sites in its intron 3 region. We also found that NFI-mediated regulation of CAST depends on NFI's phosphorylation state. We noted that occupation of CAST intron 3 by hypophosphorylated NFI results in increased activation of an alternative promoter. This activation resulted in higher levels of CAST transcript variants, leading to increased levels of CAST protein that lacks the N-terminal XL domain. CAST was primarily present in the cytoplasm of NFI-hypophosphorylated MG cells, with a predominantly perinuclear immunostaining pattern. NFI knockdown in NFI-hypophosphorylated MG cells increased CAST levels at the plasma membrane. These results suggest that NFI plays an integral role in the regulation of CAST variants and CAST subcellular distribution. Along with the previous findings indicating that NFI activity is regulated by calcineurin, these results provide a foundation for further investigations into the possibility of regulatory cross-talk between NFI and the CAST/calpain/calcineurin signaling pathway in MG cells.

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“…A previous study reported the alteration of striatal dopaminergic function in glioma development ( 30 ). Furthermore, dysregulation of serine/threonine phosphatase calcineurin has also been reported in grade IV astrocytoma tumor tissue ( 31 ). The enrichment analysis results further confirmed the effects of the dysregulated miRNAs.…”

Section: Discussionmentioning

confidence: 99%

Identification of dysregulated miRNAs and their regulatory signature in glioma patients using the partial least squares method

Shou

2014

Experimental and Therapeutic Medicine

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Using microarray data, the present study identified differentially expressed microRNAs (miRNAs) and evaluated their regulatory characteristics in high-grade glioma patients, with the aim to further the understanding into the underlying etiology of the condition. Previously, studies have generally implemented regression or variance analysis, which ignores various background biological factors. However, in the present study, analysis was performed with microarray data collected from the Gene Expression Omnibus database using a partial least squares-based method, which is more sensitive in handling microarray data. Among the six identified differentially expressed miRNAs, hsa-miR-21 and hsa-miR-612 have been previously reported to be associated with glioma. In addition, the remaining miRNAs, hsa-miR-4680, hsa-miR-1908, hsa-miR-4656 and hsa-miR-4467, may also contribute to glioma progression since they are all associated with the tumorigenesis of other types of cancer. Moreover, the expression levels of hsa-miR-1908, hsa-miR-4656 and hsa-miR-4680 have been identified to significantly correlate with the survival rate. Enrichment analysis of the dysregulated target genes revealed that the selected miRNAs primarily affect biological processes in the nervous system and the protein phosphorylation process. Therefore, the results may offer a new understanding into the pathogenesis of high-grade glioma.

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Calcineurin Regulates Nuclear Factor I Dephosphorylation and Activity in Malignant Glioma Cell Lines

Cited by 17 publications

References 81 publications

Sleeping Beauty Mouse Models Identify Candidate Genes Involved in Gliomagenesis

Sleeping Beauty Mouse Models Identify Candidate Genes Involved in Gliomagenesis

Effects of nuclear factor I phosphorylation on calpastatin (CAST) gene variant expression and subcellular distribution in malignant glioma cells

Identification of dysregulated miRNAs and their regulatory signature in glioma patients using the partial least squares method

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