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Inositol 1,3,4,5-Tetrakisphosphate Controls Proapoptotic Bim Gene Expression and Survival in B Cells

Yoann Maréchal, Xavier Pesesse, Yonghui Jia, Valérie Pouillon, David Pérez-Morga, Julien Daniel, Shozo Izui, Peter J. Cullen, Oberdan Leo, Hongbo R. Luo, Christophe Erneux and Stéphane Schurmans
Proceedings of the National Academy of Sciences of the United States of America
Vol. 104, No. 35 (Aug. 28, 2007), pp. 13978-13983
Stable URL: http://www.jstor.org/stable/25436607
Page Count: 6
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Since scans are not currently available to screen readers, please contact JSTOR User Support for access. We'll provide a PDF copy for your screen reader.
Inositol 1,3,4,5-Tetrakisphosphate Controls Proapoptotic Bim Gene Expression and Survival in B Cells
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Abstract

The contribution of the B isoform of inositol 1,4,5-trisphosphate [Ins(1,4,5)P₃] 3-kinase (or Itpkb) and inositol 1,3,4,5-tetrakisphosphate [Ins(1,3,4,5,)P₄], its reaction product, to B cell function and development remains unknown. Here, we show that mice deficient in Itpkb have defects in B cell survival leading to specific and intrinsic developmental alterations in the B cell lineage and antigen unresponsiveness in vivo. The decreased B cell survival is associated with a decreased phosphorylation of Erk1/2 and increased Bim gene expression. B cell survival, development, and antigen responsiveness are normalized in parallel to reduced expression of Bim in $Itpkb^{-/-}$ $Bim^{+/-}$ mice. Analysis of the signaling pathway downstream of Itpkb revealed that Ins(1,3,4,5)P₄ regulates subcellular distribution of Rasa3, a Ras GTPase-activating protein acting as an Ins(1,3,4,5)P₄ receptor. Together, our results indicate that Itpkb and Ins(1,3,4,5)P₄ mediate a survival signal in B cells via a Rasa3-Erk signaling pathway controlling proapoptotic Bim gene expression.

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