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Inositol 1,3,4,5-tetrakisphosphate controls proapoptotic Bim gene expression and survival in B cells

Marechal, Yoann
Pesesse, Xavier
Jia, Yonghui
Pouillon, Valerie
Perez-Morga, David
Daniel, Julien
Cullen, P. J.
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Published in Proceedings of the National Academy of Sciences. 2007, vol. 104, no. 35, p. 13978-13983
Abstract The contribution of the B isoform of inositol 1,4,5-trisphosphate [Ins(1,4,5)P(3)] 3-kinase (or Itpkb) and inositol 1,3,4,5-tetrakisphosphate [Ins(1,3,4,5)P(4)], 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)P(4) regulates subcellular distribution of Rasa3, a Ras GTPase-activating protein acting as an Ins(1,3,4,5)P(4) receptor. Together, our results indicate that Itpkb and Ins(1,3,4,5)P(4) mediate a survival signal in B cells via a Rasa3-Erk signaling pathway controlling proapoptotic Bim gene expression.
Keywords AnimalsApoptosisApoptosis Regulatory Proteins/deficiency/*geneticsB-Lymphocyte Subsets/cytology/immunology/physiologyB-Lymphocytes/*cytology/immunology/*physiologyBone Marrow/immunologyCell SurvivalGene Expression RegulationImmunoglobulin D/analysisImmunoglobulin M/analysisInositol Phosphates/*pharmacologyMembrane Proteins/deficiency/*geneticsMiceMice, KnockoutPhosphotransferases (Alcohol Group Acceptor)/deficiency/*geneticsProto-Oncogene Proteins/deficiency/*geneticsReverse Transcriptase Polymerase Chain ReactionSpleen/immunology
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PMID: 17709751
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