RRC ID 12758
著者 Matsuda S, Mikami Y, Ohtani M, Fujiwara M, Hirata Y, Minowa A, Terauchi Y, Kadowaki T, Koyasu S.
タイトル Critical role of class IA PI3K for c-Rel expression in B lymphocytes.
ジャーナル 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.
巻・号 113(5)
ページ 1037-44
公開日 2009-1-29
DOI 10.1182/blood-2008-06-163725
PII S0006-4971(20)37777-6
PMID 18927440
MeSH Active Transport, Cell Nucleus / physiology Agammaglobulinaemia Tyrosine Kinase 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 17.794
引用数 15
WOS 分野 HEMATOLOGY
リソース情報
遺伝子材料 pCAG-HIVgp (RDB04394) pCMV-VSV-G-RSV-Rev (RDB04393)