RRC ID 12758
Author Matsuda S, Mikami Y, Ohtani M, Fujiwara M, Hirata Y, Minowa A, Terauchi Y, Kadowaki T, Koyasu S.
Title Critical role of class IA PI3K for c-Rel expression in B lymphocytes.
Journal Blood
Abstract The fact that the Xid mutation of Btk impairs the ability of pleckstrin homology domain of Btk to bind phosphatidylinositol-(3,4,5)-trisphosphate, a product of class IA phosphoinositide-3 kinases (PI3Ks), has been considered strong evidence for the hypothesis that Btk functions downstream of PI3Ks. We demonstrate here that the Xid mutation renders the Btk protein unstable. Furthermore, class IA PI3K- and Btk-deficient mice show different phenotypes in B-cell development, collectively indicating that PI3Ks and Btk differentially function in BCR signal transduction. Nevertheless, both PI3K and Btk are required for the activation of NF-kappaB, a critical transcription factor family for B-cell development and function. We demonstrate that PI3Ks maintain the expression of NF-kappaB proteins, whereas Btk is known to be essential for IkappaB degradation and the translocation of NF-kappaB to the nucleus. The loss of PI3K activity results in marked reduction of c-Rel and to a lesser extent RelA expression. The lentivirus-mediated introduction of c-Rel corrects both developmental and proliferative defects in response to BCR stimulation in class IA PI3K-deficient B cells. These results show that the PI3K-mediated control of c-Rel expression is essential for B-cell functions.
Volume 113(5)
Pages 1037-44
Published 2009-1-29
DOI 10.1182/blood-2008-06-163725
PII blood-2008-06-163725
PMID 18927440
MeSH Active Transport, Cell Nucleus / physiology Animals B-Lymphocytes / metabolism* Cell Nucleus / genetics Cell Nucleus / metabolism* Enzyme Stability / physiology Gene Expression Regulation / physiology* I-kappa B Proteins / genetics I-kappa B Proteins / metabolism Mice Mice, Inbred BALB C Mice, Knockout Mutation Phosphatidylinositol 3-Kinases / genetics Phosphatidylinositol 3-Kinases / metabolism* Protein Structure, Tertiary / physiology Protein-Tyrosine Kinases / genetics Protein-Tyrosine Kinases / metabolism* Proto-Oncogene Proteins c-rel / biosynthesis* Proto-Oncogene Proteins c-rel / genetics Receptors, Antigen, B-Cell / genetics Receptors, Antigen, B-Cell / metabolism Signal Transduction / physiology* Transcription Factor RelA / genetics Transcription Factor RelA / metabolism
IF 16.601
Times Cited 10
DNA material pCAG-HIVgp (RDB04394) pCMV-VSV-G-RSV-Rev (RDB04393)