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A c-Myc/miR17-92/Pten axis controls PI3K-mediated positive and negative selection in B cell development and reconstitutes CD19 deficiency

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Item Type:Article
Title:A c-Myc/miR17-92/Pten axis controls PI3K-mediated positive and negative selection in B cell development and reconstitutes CD19 deficiency
Creators Name:Benhamou, D. and Labi, V. and Novak, R. and Dai, I. and Shafir-Alon, S. and Weiss, A. and Gaujoux, R. and Arnold, R. and Shen-Orr, S.S. and Rajewsky, K. and Melamed, D.
Abstract:PI3K activity determines positive and negative selection of B cells, a key process for immune tolerance and B cell maturation. Activation of PI3K is balanced by phosphatase and tensin homolog (Pten), the PI3K's main antagonistic phosphatase. Yet, the extent of feedback regulation between PI3K activity and Pten expression during B cell development is unclear. Here, we show that PI3K control of this process is achieved post-transcriptionally by an axis composed of a transcription factor (c-Myc), a microRNA (miR17-92), and Pten. Enhancing activation of this axis through overexpression of miR17-92 reconstitutes the impaired PI3K activity for positive selection in CD19-deficient B cells and restores most of the B cell developmental impairments that are evident in CD19-deficient mice. Using a genetic approach of deletion and complementation, we show that the c-Myc/miR17-92/Pten axis critically controls PI3K activity and the sensitivity of immature B cells to negative selection imposed by activation-induced cell death.
Keywords:Antigens, CD19, B-Lymphocytes, Cell Death, Cells, Cultured, DEAD-Box RNA Helicases, Genetic Complementation Test, Heterozygote, MicroRNAs, PTEN Phosphohydrolase, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins C-myc, Ribonuclease III, Signal Transduction, Animals, Mice, Inbred C57BL, Mice, Transgenic
Source:Cell Reports
ISSN:2211-1247
Publisher:Cell Press / Elsevier (U.S.A.)
Volume:16
Number:2
Page Range:419-431
Date:12 July 2016
Official Publication:https://doi.org/10.1016/j.celrep.2016.05.084
PubMed:View item in PubMed

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