Transgenic Expression of MicroRNA-185 Causes a Developmental Arrest of T Cells by Targeting Multiple Genes Including Mzb1

Belkaya, Serkan; Murray, Sean; Eitson, Jennifer L.; Morena, M. Teresa de la; Forman, James A.; Oers, Nicolai S. C. van

doi:10.1074/jbc.m113.503532

Cited by 36 publications

(34 citation statements)

References 35 publications

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“…MiR-185 targeted Mzb1, NF-ATc3, and Camk4 in developing thymocytes, with Mzb1 reduced 5-fold. This reduction causes a T cell receptor-dependent increase in intracellular calcium levels [39]. This agrees with previous work demonstrating that Mzb1 is an endoplasmic reticulum calcium regulator, with high levels of Mzb1 reducing calcium influx [40].…”

Section: Discussionsupporting

confidence: 91%

“…In mouse models, reductions in miR-185 increase the expression of one of its target, Bruton’s tyrosine kinase, leading to autoantibody production by B cells [38]. In our miR-185 over-expression model in T cells, elevated miR-185 caused a dose-dependent T cell lymphopenia [39]. MiR-185 targeted Mzb1, NF-ATc3, and Camk4 in developing thymocytes, with Mzb1 reduced 5-fold.…”

Section: Discussionmentioning

confidence: 99%

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Signature MicroRNA expression patterns identified in humans with 22q11.2 deletion/DiGeorge syndrome

Morena

Eitson

Dozmorov

et al. 2013

Clinical Immunology

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Patients with 22q11.2 deletion syndrome have heterogeneous clinical presentations including immunodeficiency, cardiac anomalies, and hypocalcemia. The syndrome arises from hemizygous deletions of up to 3 Mb on chromosome 22q11.2, a region that contains 60 genes and 4 microRNAs. MicroRNAs are important post-transcriptional regulators of gene expression, with mutations in several microRNAs causal to specific human diseases. We characterized the microRNA expression patterns in the peripheral blood of patients with 22q11.2 deletion syndrome (n=31) compared to normal controls (n=22). Eighteen microRNAs had a statistically significant differential expression (p<0.05), with miR-185 expressed at 0.4× normal levels. The 22q11.2 deletion syndrome cohort exhibited microRNA expression hyper-variability and group dysregulation. Selected microRNAs distinguished patients with cardiac anomalies, hypocalcemia, and/or low circulating T cell counts. In summary, microRNA profiling of chromosome 22q11.2 deletion syndrome/DiGeorge patients revealed a signature microRNA expression pattern distinct from normal controls with clinical relevance.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Signature MicroRNA expression patterns identified in humans with 22q11.2 deletion/DiGeorge syndrome

Morena

Eitson

Dozmorov

et al. 2013

Clinical Immunology

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“…Second, miR-185 is expressed primarily in the heart, brain and kidney [26], suggesting a potential role in these tissues. Third, miR-185 is differentially expressed in the heart of pressure overload-induced cardiac hypertrophy models [12].…”

Section: Resultsmentioning

confidence: 99%

miR-185 Plays an Anti-Hypertrophic Role in the Heart via Multiple Targets in the Calcium-Signaling Pathways

et al. 2015

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MicroRNA (miRNA) is an endogenous non-coding RNA species that either inhibits RNA translation or promotes degradation of target mRNAs. miRNAs often regulate cellular signaling by targeting multiple genes within the pathways. In the present study, using Gene Set Analysis, a useful bioinformatics tool to identify miRNAs with multiple target genes in the same pathways, we identified miR-185 as a key candidate regulator of cardiac hypertrophy. Using a mouse model, we found that miR-185 was significantly down-regulated in myocardial cells during cardiac hypertrophy induced by transverse aortic constriction. To confirm that miR-185 is an anti-hypertrophic miRNA, genetic manipulation studies such as overexpression and knock-down of miR-185 in neonatal rat ventricular myocytes were conducted. The results showed that up-regulation of miR-185 led to anti-hypertrophic effects, while down-regulation led to pro-hypertrophic effects, suggesting that miR-185 has an anti-hypertrophic role in the heart. Our study further identified Camk2d, Ncx1, and Nfatc3 as direct targets of miR-185. The activity of Nuclear Factor of Activated T-cell (NFAT) and calcium/calmodulin-dependent protein kinase II delta (CaMKIIδ) was negatively regulated by miR-185 as assessed by NFAT-luciferase activity and western blotting. The expression of phospho-phospholamban (Thr-17), a marker of CaMKIIδ activity, was also significantly reduced by miR-185. In conclusion, miR-185 effectively blocked cardiac hypertrophy signaling through multiple targets, rendering it a potential drug target for diseases such as heart failure.

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“…MZB1 , which was first identified as a gene induced during the differentiation of B cells to plasma cells, regulates the correct surface presentation and secretion of mature IgM . MZB1 is highly expressed in marginal zone B (MZB) cells and antibody secreting cells .…”

Section: Discussionmentioning

confidence: 99%

Epigenetic suppression of the immunoregulator MZB1 is associated with the malignant phenotype of gastric cancer

Kanda

Tanaka

Kobayashi

et al. 2016

Intl Journal of Cancer

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Prediction of tumor recurrence after curative resection is critical for determining the prognosis of patients with gastric cancer (GC). The initiation and progression of GC are associated with inappropriate immune responses caused by chronic inflammation of the gastric mucosa. To identify immunoregulatory molecules involved in GC progression, GC cell lines and 200 pairs of tumor and normal tissues from patients with GC were analyzed for gene expression, amplification and methylation as well as function of a differentially expressed gene. The transcriptome analysis revealed that marginal zone B and B1 cell specific protein (MZB1) was expressed at significantly decreased levels in primary GC tissues when compared with the corresponding normal gastric mucosa. PCR array analysis exploring genes expressed cooperatively with MZB1 revealed that differential expression of MZB1 mRNA in GC cell lines correlated positively with the levels of the mRNAs encoding estrogen receptor 1 and desumoylating isopeptidase 1. Hypermethylation of the MZB1 promoter was frequent in cell lines with decreased levels of MZB1 mRNA. siRNA-mediated knockdown of MZB1 significantly increased proliferation, invasion and migration of GC cell lines. Low MZB1 expression was an independent prognostic factor for recurrence after curative gastrectomy and was associated significantly with increased hematogenous recurrence. MZB1 acts as a suppressor of GC. Low MZB1 expression in the primary GC tissue is predictive of recurrence after curative resection.

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Transgenic Expression of MicroRNA-185 Causes a Developmental Arrest of T Cells by Targeting Multiple Genes Including Mzb1

Cited by 36 publications

References 35 publications

Signature MicroRNA expression patterns identified in humans with 22q11.2 deletion/DiGeorge syndrome

Signature MicroRNA expression patterns identified in humans with 22q11.2 deletion/DiGeorge syndrome

miR-185 Plays an Anti-Hypertrophic Role in the Heart via Multiple Targets in the Calcium-Signaling Pathways

Epigenetic suppression of the immunoregulator MZB1 is associated with the malignant phenotype of gastric cancer

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