Micro-RNA Feedback Loops Modulating the Calcineurin/NFAT Signaling Pathway
Abstract
:1. Introduction
2. Results
2.1. miRNAs Targeting the Calcineurin/NFAT Signaling Pathway
2.2. miRNAs Induced by NFAT Transcription Factor Family
2.3. miRNAs in Negative or Positive Feedback Loop to Modulate the Calcineurin/NFAT Signaling Pathway Activity
3. Discussion
4. Materials and Methods
4.1. Computational Prediction of miRNA Targeting Members of the Calcineurin/NFAT Pathway
4.2. Experimental Validation Data on miRNA Targets
4.3. miRNA Expressed in PBMCs
4.4. miRNA Promoter Sequences and NFAT Transcription Factor Binding Site
4.5. Upregulated miRNA Selection from Activated Human T Cells
5. Conclusions
Supplementary Materials
Acknowledgments
Author Contributions
Conflicts of Interest
Abbreviations
NFAT | Nuclear factor of activated T cells |
PPP3CA | Calmodulin-Dependent Calcineurin A Subunit Alpha Isoform |
RCAN | RCAN Family Member/ Down Syndrome Candidate Region 1-Like Protein |
GSK | Glycogen Synthase Kinase |
DYRK1A | Dual-Specificity Tyrosine-(Y)-Phosphorylation Regulated Kinase 1A |
HOMER2 | Homer Scaffolding Protein |
ITPR1 | Inositol 1,4,5-Trisphosphate Receptor, Type 1 |
MAP3K7 | Mitogen-Activated Protein Kinase Kinase Kinase 7 |
TAB | TGF-Beta Activated Kinase 1/MAP3K7 Binding Protein |
CSNK1A1 | Casein Kinase 1, Alpha 1 |
LRRK | Lrrk Leucine-rich repeat kinase |
CABIN | Calcineurin Binding Protein |
AKAP | A-kinase anchor proteins |
CALM | Calmodulin |
STIM | stromal interaction molecule |
ORAI | Calcium Release-Activated Calcium Modulator |
miRNA | micro RNA |
RPM | Reads Per Million |
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Gene | Description | |
---|---|---|
NFATc1 | Family of transcription factors that are expressed in the vertebrates. These transcription factors induce expression of cytokine genes important for immune response. | [38,52] |
NFATc2 | ||
NFATc3 | ||
NFATc4 | ||
PPP3CA | Calcium-dependent, calmodulin-stimulated protein phosphatase. It dephosphorylates the NFAT transcription factors and facilitates nuclear transport of NFAT. | [33] |
PPP3CB | ||
PPP3R1 | ||
PPP3R2 | ||
RCAN1 | Transcribed by NFAT transcription factor and interacts with calcineurin to inhibit calcineurin-dependent signaling pathways. | [38,53] |
GSK3B | Phosphorylates NFAT into its inactive form and facilitates the cytoplasmic transport of NFAT. | [38,54,55] |
DYRK1A | ||
HOMER2 | Is a negative regulator of T cell activation and binds with NFAT to compete with calcineurin binding. | [34] |
ITPR1 | Intracellular channel that mediates calcium release from the endoplasmic reticulum. | [38,56] |
MAP3K7 | Selectively induces calcineurin-NFAT signaling through direct phosphorylation of RCAN1. | [35] |
TAB1 | Phosphorylated RCAN1 and inhibits RCAN1 from binding to calcineurin. | [35] |
TAB2 | ||
CSNK1A1/CK1 | Works as a negative inhibitor of the NFAT by phosphorylation and mediates its cytoplasmic translocation. | [57] |
LRRK2 | Negative regulator of the transcription factor NFAT and is a component of a complex that includes the large non-coding RNA NRON (an NFAT repressor). | [58] |
CABIN1 | Binds specifically to the activated form of calcineurin and inhibits calcineurin-mediated signal transduction and NFAT nuclear translocation. | [36] |
AKAP5 | Inhibits calcineurin-dependent dephosphorylation of NFAT | [59] |
CALM1 | Calmodulin is a calcium binding protein that activates the calcineurin. | [37] |
STIM1 | Ca2+ sensor proteins on the endoplasmic reticulum, which is an indispensable part in the activation of store-operated Ca2+ channels (SOC). | [60] |
ORAI1 | Calcium channel subunit that is activated by the calcium sensor STIM1 when calcium stores are depleted. | [61] |
miRNAs Involved in Feedback Loops | Target Genes | miRNA Average Expression in Activated T Cells (RPM) |
---|---|---|
hsa-miR-21-3p | CALM1 | 191 |
hsa-let-7b-5p | NFATC1 | 8617 |
hsa-miR-17-5p | PPP3R1 | 778 |
hsa-miR-17-3p | STIM1 | 859 |
hsa-miR-19a-3p | ITPR1 | 4379 |
hsa-miR-92b-3p | ITPR1 | 254 |
hsa-miR-21-5p | CSNK1A1 | 372,670 |
hsa-miR-181c-5p | CSNK1A1 | 321 |
hsa-let-7c-5p | GSK3A | 889 |
hsa-let-7b-3p | GSK3B | 77 |
hsa-miR-155-5p | GSK3B | 282,932 |
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Kannambath, S. Micro-RNA Feedback Loops Modulating the Calcineurin/NFAT Signaling Pathway. Non-Coding RNA 2016, 2, 3. https://doi.org/10.3390/ncrna2020003
Kannambath S. Micro-RNA Feedback Loops Modulating the Calcineurin/NFAT Signaling Pathway. Non-Coding RNA. 2016; 2(2):3. https://doi.org/10.3390/ncrna2020003
Chicago/Turabian StyleKannambath, Shichina. 2016. "Micro-RNA Feedback Loops Modulating the Calcineurin/NFAT Signaling Pathway" Non-Coding RNA 2, no. 2: 3. https://doi.org/10.3390/ncrna2020003