Dataset Information

MiRNAs Are Essential for the Regulation of the PI3K/AKT/FOXO Pathway and Receptor Editing during B Cell Maturation.

ABSTRACT: B cell development is a tightly regulated process dependent on sequential rearrangements of immunoglobulin loci that encode the antigen receptor. To elucidate the role of microRNAs (miRNAs) in the orchestration of B cell development, we ablated all miRNAs at the earliest stage of B cell development by conditionally targeting the enzymes critical for RNAi in early B cell precursors. Absence of any one of these enzymes led to a block at the pro- to pre-B cell transition due to increased apoptosis and a failure of pre-B cells to proliferate. Expression of a Bcl2 transgene allowed for partial rescue of B cell development, however, the majority of the rescued B cells had low surface immunoglobulin expression with evidence of ongoing light chain editing. Our analysis revealed that miRNAs are critical for the regulation of the PTEN-AKT-FOXO1 pathway that in turn controls Rag expression during B cell development.

SUBMITTER: Coffre M

PROVIDER: S-EPMC5679080 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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miRNAs Are Essential for the Regulation of the PI3K/AKT/FOXO Pathway and Receptor Editing during B Cell Maturation.

Coffre Maryaline M Benhamou David D Rieß David D Blumenberg Lili L Snetkova Valentina V Hines Marcus J MJ Chakraborty Tirtha T Bajwa Sofia S Jensen Kari K Chong Mark M W MMW Getu Lelise L Silverman Gregg J GJ Blelloch Robert R Littman Dan R DR Calado Dinis D Melamed Doron D Skok Jane A JA Rajewsky Klaus K Koralov Sergei B SB

Cell reports 20161101 9

B cell development is a tightly regulated process dependent on sequential rearrangements of immunoglobulin loci that encode the antigen receptor. To elucidate the role of microRNAs (miRNAs) in the orchestration of B cell development, we ablated all miRNAs at the earliest stage of B cell development by conditionally targeting the enzymes critical for RNAi in early B cell precursors. Absence of any one of these enzymes led to a block at the pro- to pre-B cell transition due to increased apoptosis ...[more]

PMID: 27880903

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Project description:The early diagnosis and treatment of liver hepatocellular carcinoma (LIHC) remains a major challenge. Therefore, it is of great significance to strengthen basic research on LIHC in order to improve the prevention and treatment of the disease. Numerous studies have indicated that the PI3K/Akt and FoxO signaling pathways mediate proliferation, survival and migration during the development of LIHC. Therefore, they have become a target for LIHC treatment. Furthermore, let-7c has been demonstrated to repress cell proliferation, migration and invasion, and to induce G1 phase arrest and apoptosis of LIHC cells. However, the mechanism of its action is not clear. In the present study, the association between let-7c and the PI3K/Akt/FoxO signaling pathway, as well as their roles in the development of LIHC were investigated using The Cancer Genome Atlas and various public databases (Tumor-miRNA-Pathway, OncomiR, DIANA-TarBase v8, KOBAS 3.0, ONCOMINE, Kaplan-Meier plotter, LinkedOmics, UALCAN and cBioPortal). The effects of let-7c-5p on PI3K/Akt/FoxO signaling pathway-related target genes were analyzed following overexpression of let-7c-5p in the MHCC-97H cell line via reverse transcription-quantitative PCR, and the let-7c-5p target genes belonging to the PI3K/Akt/FOXO signaling pathway in LIHC were screened out. GO and KEGG enrichment analyses of these target genes was performed using g:Profiler, gOST. In addition, GeneMANIA and Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) databases were used to determine the gene-gene and protein-protein interaction networks, respectively. The data demonstrated that cyclin B2 (CCNB2), cyclin E2 (CCNE2), cyclin dependent kinase 4 (CDK4), homer scaffold protein 1 (HOMER1), heat shock protein 90 α family class A member 1 (HSP90AA1), neuroblastoma RAS viral oncogene homolog (NRAS), protein phosphatase 2 catalytic subunit α (PPP2CA), protein kinase AMP-activated catalytic subunit α2 (PRKAA2) and Rac family small GTPase 1 (RAC1) may be target genes of let-7c-5p. These genes, particularly CCNE2, were associated with poor overall survival and could be promising candidate biomarkers for disease and poor prognosis in LIHC. Among them, seven genes (CCNE2, CDK4, HSP90AA1, NRAS, PPP2CA, PRKAA2 and RAC1) belonged to the PI3K-Akt signaling pathway and four genes (CCNB2, HOMER1, NRAS and PRKAA2) belonged to the FoxO signaling pathway. The majority of these genes were closely associated with the cell cycle and their elevated expression may aggravate cell cycle disorders. Therefore, let-7c may be considered to be an anti-oncogene of LIHC. The present study may provide novel targets and strategies for the diagnosis and treatment of LIHC.

Project description:BACKGROUND:Cultured epidermal stem cells (Epi-SCs) and skin-derived precursors (SKPs) were capable of reconstituting functional hair follicles after implantation, while the signaling pathways that regulate neogenic hair follicle formation are poorly investigated. In this study, we aimed to understand the interactions between Epi-SCs and SKPs during skin organoid formation and to uncover key signal pathways crucial for de novo hair follicle regeneration. METHODS:To track their fate after transplantation, Epi-SCs derived from neonatal C57BL/6 mice were labeled with tdTomato, and SKPs were isolated from neonatal C57BL/6/GFP mice. A mixture of Epi-SCs-tdTomato and SKPs-EGFP in Matrigel was observed under two-photon microscope in culture and after implantation into excisional wounds in nude mice, to observe dynamic migrations of the cells during hair follicle morphogenesis. Signaling communications between the two cell populations were examined by RNA-Seq analysis. Potential signaling pathways revealed by the analysis were validated by targeting the pathways using specific inhibitors to observe a functional loss in de novo hair follicle formation. RESULTS:Two-photon microscopy analysis indicated that when Epi-SCs and SKPs were mixed in Matrigel and cultured, they underwent dynamic migrations resulting in the formation of a bilayer skin-like structure (skin organoid), where Epi-SCs positioned themselves in the outer layer; when the mixture of Epi-SCs and SKPs was grafted into excisional wounds in nude mice, a bilayer structure resembling the epidermis and the dermis formed at the 5th day, and de novo hair follicles generated subsequently. RNA-Seq analysis of the two cell types after incubation in mixture revealed dramatic alterations in gene transcriptome, where PI3K-Akt signaling pathway in Epi-SCs was significantly upregulated; meanwhile, elevated expressions of several growth factors and cytokine potentially activating PI3K were found in SKPs, suggesting active reciprocal communications between them. In addition, inhibition of PI3K or Akt by specific inhibitors markedly suppressed the hair follicle regeneration mediated by Epi-SCs and SKPs. CONCLUSIONS:Our data indicate that the PI3K-Akt signaling pathway plays a crucial role in de novo hair follicle regeneration, and the finding may suggest potential therapeutic applications in enhancing hair regeneration.

Dataset Information

MiRNAs Are Essential for the Regulation of the PI3K/AKT/FOXO Pathway and Receptor Editing during B Cell Maturation.

Publications

miRNAs Are Essential for the Regulation of the PI3K/AKT/FOXO Pathway and Receptor Editing during B Cell Maturation.

Similar Datasets

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