Dataset Information

MicroRNA-205 Maintains T Cell Development following Stress by Regulating Forkhead Box N1 and Selected Chemokines.

ABSTRACT: The thymus, an organ responsible for T cell development, is one of the more stress-sensitive tissues in the body. Stress, in the form of infections, radiation exposure, and steroids, impairs thymic epithelial cell (TEC) functions and induces the programmed cell death of immature thymocytes. MicroRNAs are small noncoding RNAs involved in tissue repair and homeostasis, with several supporting T cell development. We report that miR-205, an epithelial-specific miR, maintains thymopoiesis following inflammatory perturbations. Thus, the activation of diverse pattern recognition receptors in mice causes a more severe thymic hypoplasia and delayed T cell recovery when miR-205 is conditionally ablated in TECs. Gene expression comparisons in the TECs with/without miR-205 revealed a significant differential regulation of chemokine/chemokine receptor pathways, antigen processing components, and changes in the Wnt signaling system. This was partly a consequence of reduced expression of the transcriptional regulator of epithelial cell function, Forkhead Box N1 (Foxn1), and its two regulated targets, stem cell factor and ccl25, following stress. miR-205 mimics supplemented into miR-205-deficient fetal thymic organ cultures restored Foxn1 expression along with ccl25 and stem cell factor A number of putative targets of miR-205 were up-regulated in TECs lacking miR-205, consistent with an important role for this miR in supporting T cell development in response to stress.

SUBMITTER: Hoover AR

PROVIDER: S-EPMC5087740 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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MicroRNA-205 Maintains T Cell Development following Stress by Regulating Forkhead Box N1 and Selected Chemokines.

Hoover Ashley R AR Dozmorov Igor I MacLeod Jessica J Du Qiumei Q de la Morena M Teresa MT Forbess Joseph J Guleserian Kristine K Cleaver Ondine B OB van Oers Nicolai S C NS

The Journal of biological chemistry 20160919 44

The thymus, an organ responsible for T cell development, is one of the more stress-sensitive tissues in the body. Stress, in the form of infections, radiation exposure, and steroids, impairs thymic epithelial cell (TEC) functions and induces the programmed cell death of immature thymocytes. MicroRNAs are small noncoding RNAs involved in tissue repair and homeostasis, with several supporting T cell development. We report that miR-205, an epithelial-specific miR, maintains thymopoiesis following i ...[more]

PMID: 27646003

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Project description:Glioblastoma multiforme (GBM) is the most common type of malignant brain tumor. GBM is currently treated with temozolomide (TMZ), although patients often exhibit resistance to this agent. Although several mechanisms underlying the resistance of GBM to TMZ have been identified, the combination of these mechanisms is not sufficient to fully account for this phenomenon. Our previous study demonstrated that knocking down the Forkhead box protein O3a (FoxO3a) gene, a member of the FoxO subfamily of transcription factors, resulted in glioma cell sensitization to TMZ, accompanied by reduced levels of nuclear β-catenin. The aim of the present study was to specify how FoxO3a and β-catenin are implicated in glioma cell TMZ resistance. Using the U87 and U251 parental cell lines (also designated as sensitive cell lines) and corresponding resistant cell lines (U87-TR and U251-TR, generated by repeated TMZ treatments), coupled with a combined knockdown/overexpression strategy, it was revealed that FoxO3a or β-catenin overexpression in TMZ-treated U87 and U251 cells markedly increased cellular proliferation; co-expression of both FoxO3a and β-catenin resulted in the highest increase. Knockdown of either FoxO3a or β-catenin in U87-TR and U251-TR cells led to a significant decrease in cell viability, which was rescued by the re-expression of FoxO3a in FoxO3a-knockdown cells. Subsequent experiments demonstrated that, in U87-TR and U251-TR cells, FoxO3a knockdown significantly reduced the protein levels of matrix metallopeptidase (MMP)9, while overexpression of FoxO3a in U87 and U251 cells enhanced the nuclear accumulation of β-catenin, concomitantly with an increase in MMP9 levels. Furthermore, MMP9 knockdown markedly reduced the levels of nuclear β-catenin. Collectively, the findings of the present study suggest that FoxO3a may regulate the nuclear accumulation of β-catenin by modulating MMP9 expression, thereby rendering glioblastoma cells resistant to TMZ, and may provide unique molecular insights into the mechanisms underlying the development of TMZ resistance in GBM.

Dataset Information

MicroRNA-205 Maintains T Cell Development following Stress by Regulating Forkhead Box N1 and Selected Chemokines.

Publications

MicroRNA-205 Maintains T Cell Development following Stress by Regulating Forkhead Box N1 and Selected Chemokines.

Similar Datasets

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