Biotin supplementation decreases the expression of the SERCA3 gene (ATP2A3) in Jurkat cells, thus, triggering unfolded protein response

Griffin, Jacob B.; Rodriguez-Melendez, Rocio; Dode, Leonard; Wuytack, Frank; Zempleni, Janos

doi:10.1016/j.jnutbio.2005.05.005

Cited by 18 publications

(11 citation statements)

References 63 publications

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“…Nitric oxide (NO) is a fundamental signaling molecule involved in several physiological processes including host defense, and the regulation of vascular tone as well as a potent cytotoxic effector involved in human diseases pathogenesis (62), Griffin et al showed that decreased ATP2A3 expression induces unfolded protein response (UPR) in Jurkat cells (65) and our sequencing results also observed that down-regulation of ATP2A3 resulted in induction of unfolded protein response in these cells. Recently, researchers showed decreased PDE2A expression leads to increased accumulation of cAMP and myocardial contractility after beta-adrenogenic receptor stimulation (66, 67).…”

Section: Discussionsupporting

confidence: 52%

Impaired Regulation of Redox Transcriptome during the Differentiation of iPSCs into Induced Cardiomyocytes (iCMs)

Shanmugam

Crossman

Rajasingh

et al. 2019

Preprint

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Background: Reprogramming of somatic cells into pluripotent stem cells (iPSC) and subsequent differentiation into iPSC-derived cardiomyocytes (iCM) seems to be a promising strategy for cardiac regenerative therapy. However, recent failure or poor outcomes in cardiac cell therapy warrants further investigation focusing on the infarction/wound environment (site of healing) to improve the cardiac regenerative medicine. Here, using next generation sequencing (NGS), we analyzed the global transcriptome to discover the unidentified genes/pathways that are crucial for cell survival, cytoprotection and mitochondrial dynamics during the differentiation of iPSC into iCM.Methods: High throughput NGS was performed RNA from human iPSCs and iCMs (n=3/group) and analyzed the global changes in the transcriptome during differentiation. Furthermore, Ingenuity Pathway Analysis (IPA) and Gene Ontology (GO) for biological process were performed to understand the transcriptional networks that are involved during iCM differentiation. RNA-seq data were further validated by qRT-PCR analyses. Results:Global transcriptome analysis revealed that ~9,290 genes (log 2 FC >2) were significantly altered in human iCMs compared to the parent iPSCs, in which 4,784 transcripts were substantially upregulated and 4,506 transcripts were down-regulated during differentiation.GO enrichment and IPA analyses revealed the top 10 regulatory networks (i.e. hierarchical order) involved in differentiation of iCMs including cardiomyocyte remodeling, integrin-linked kinase signaling, Rho family of GTPases, etc. Surprisingly, none of the top 10 pathways listed the genes liable for redox signaling networks that are crucial for the basal cellular redox homeostasis, Nrf2-dependent antioxidant defense, mitochondrial functions and cell survival. Our deeper and unbiased analysis of this data revealed that the genes involved in above canonical signaling pathways are found in the middle of the inverted vertical cone. Of note, although these pathways are significantly altered during the differentiation (of iPS into cardiomyocytes), a majority of them are ranked low in the hierarchical list (>150). Validation of the randomly selected genes representing various pathways real-time qPCR confirmed the global transcriptome changes observed in NGS. Conclusion:We highlight the significance of Nrf2-redox and mitochondrial transcriptome during differentiation of iPSC into iCMs. Thus, targeting the redox signaling mechanisms in iCMs may enhance their efficiency for cell therapy and improved myocardial repair.180 genes were detected out of 230 genes known to constitute this pathway, whereas 58 genes were increased and 56 genes were decreased. From this list, the top 15 up and down-regulated genes were used to generate the heat-maps. A substantial list of genes were downregulated during cardiomyocyte differentiation including, MGST1, GSTM5, PRKCQ, PRKCB and PIK3R, while PIK3R5ACTA2, GSTM3, FMO1, ACTC1 and GSTA3 were increased during cardiomyocyte differentiation. RNA-seq data was valid...

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Section: Discussionsupporting

confidence: 52%

Impaired Regulation of Redox Transcriptome during the Differentiation of iPSCs into Induced Cardiomyocytes (iCMs)

Shanmugam

Crossman

Rajasingh

et al. 2019

Preprint

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“…Given that Sp3 may act as transcriptional repressor, it has been proposed that effects of biotin on SERCA3 expression are mediated by the increased nuclear abundance of Sp3 in biotin-supplemented cells (58). Decreased expression of SERCA3 reduces the sequestration of calcium in the endoplasmic reticulum (ER) (83).…”

Section: Sp1 and Sp3mentioning

confidence: 99%

Uptake, Localization, and Noncarboxylase Roles of Biotin

2005

Self Cite

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Evidence is emerging that biotin participates in processes other than classical carboxylation reactions. Specifically, novel roles for biotin in cell signaling, gene expression, and chromatin structure have been identified in recent years. Human cells accumulate biotin by using both the sodium-dependent multivitamin transporter and monocarboxylate transporter 1. These transporters and other biotin-binding proteins partition biotin to compartments involved in biotin signaling: cytoplasm, mitochondria, and nuclei. The activity of cell signals such as biotinyl-AMP, Sp1 and Sp3, nuclear factor (NF)-kappaB, and receptor tyrosine kinases depends on biotin supply. Consistent with a role for biotin and its catabolites in modulating these cell signals, greater than 2000 biotin-dependent genes have been identified in various human tissues. Many biotin-dependent gene products play roles in signal transduction and localize to the cell nucleus, consistent with a role for biotin in cell signaling. Posttranscriptional events related to ribosomal activity and protein folding may further contribute to effects of biotin on gene expression. Finally, research has shown that biotinidase and holocarboxylase synthetase mediate covalent binding of biotin to histones (DNA-binding proteins), affecting chromatin structure; at least seven biotinylation sites have been identified in human histones. Biotinylation of histones appears to play a role in cell proliferation, gene silencing, and the cellular response to DNA repair. Roles for biotin in cell signaling and chromatin structure are consistent with the notion that biotin has a unique significance in cell biology.

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“…We speculate that one or more of the many biotin-dependent transcription factors participate in the regulation of the two genes (5, 9, 21). In addition, we propose that decreased expression of the sarcoplasmic/endoplasmic reticulum ATPase 3 (SERCA3) in biotin-supplemented cells decreases the transport of Ca 2+ from the cytoplasm into the endoplasmic reticulum, leading to increased concentrations of Ca 2+ in the cytoplasm (20). Cytoplasmic free Ca 2+ is known to enhance the production of NO in Jurkat cells (45).…”

Section: Discussionmentioning

confidence: 99%

“…Second, biotin deficiency causes nuclear translocation of the transcription factor NF-κB, mediating transcriptional activation of anti-apoptotic genes (9). Third, biotin supplementation decreases expression of the SERCA3 gene, thereby enhancing the levels of Ca 2+ in the cytoplasm and triggering the unfolded protein response (20). Fourth, biotin deficiency activates jun/fos signaling, activating AP1-dependent pathways (5).…”

mentioning

confidence: 99%

Nitric Oxide Signaling Depends on Biotin in Jurkat Human Lymphoma Cells

Rodriguez-Melendez

Zempleni

2009

The Journal of Nutrition

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Biotin affects gene expression through a diverse array of cell signaling pathways. Previous studies provided evidence that cGMP-dependent signaling also depends on biotin, but the mechanistic sequence of cGMP regulation by biotin is unknown. Here we tested the hypothesis that the effects of biotin in cGMP-dependent cell signaling are mediated by nitric oxide (NO). Human lymphoid (Jurkat) cells were cultured in media containing deficient (0.025 nmol/L), physiological (0.25 nmol/L), and pharmacological (10 nmol/L) concentrations of biotin for 5 wk. Both levels of intracellular biotin and NO exhibited a dose-dependent relationship in regard to biotin concentrations in culture media. Effects of biotin on NO levels were disrupted by the NO synthase (NOS) inhibitor N-monomethyl-arginine. Biotin-dependent production of NO was linked with biotin-dependent expression of endothelial and neuronal NOS, but not inducible NOS. Previous studies revealed that NO is an activator of guanylate cyclase. Consistent with these previous observations, biotin-dependent generation of NO increased the abundance of cGMP in Jurkat cells. Finally, the biotin-dependent generation of cGMP increased protein kinase G activity. Collectively this study is consistent with the hypothesis that biotin-dependent cGMP signaling in human lymphoid cells is mediated by NO.

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Biotin supplementation decreases the expression of the SERCA3 gene (ATP2A3) in Jurkat cells, thus, triggering unfolded protein response

Cited by 18 publications

References 63 publications

Impaired Regulation of Redox Transcriptome during the Differentiation of iPSCs into Induced Cardiomyocytes (iCMs)

Impaired Regulation of Redox Transcriptome during the Differentiation of iPSCs into Induced Cardiomyocytes (iCMs)

Uptake, Localization, and Noncarboxylase Roles of Biotin

Nitric Oxide Signaling Depends on Biotin in Jurkat Human Lymphoma Cells

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