TY - JOUR
T1 - Posttranscriptional regulation of Bruton's tyrosine kinase expression in antigen receptor-stimulated splenic B cells
AU - Nisitani, Sazuku
AU - Satterthwaite, Anne B.
AU - Akashi, Koichi
AU - Weissman, Irving L.
AU - Witte, Owen N.
AU - Wahl, Matthew I.
PY - 2000/3/14
Y1 - 2000/3/14
N2 - Mutation of Bruton's tyrosine kinase (Btk) causes human X-linked agammaglobulinemia and murine X-linked immunodeficiency syndrome (xid). Quantitative aspects of B lymphocyte development and function have been demonstrated to depend on Btk level in vivo by using a murine transgenic model system. A sensitive intracellular immunofluorescent assay was developed to measure Btk protein on a per cell basis to test the hypothesis that its dosage is dynamically regulated during B cell development or functional responses. Marrow-derived hematopoietic stem cells, common lymphoid progenitor cells, and developing B and myeloid lineages expressed Btk protein at comparable levels. Resting peripheral B lineage cells had a significantly lower amount of Btk than marrow-derived cells in both wild-type and xid mice. Activation of the B cell antigen receptor up-regulated Btk protein level 10- fold within several hours by a phosphatidylinositol 3-kinase-dependent, post- transcriptional mechanism. In contrast, the protein level of Btk R2BC in activated B lymphocytes from xid mice remained low. Bypass of the antigen receptor signaling pathways by treatment of cells with phorbol myristic acid and ionomycin rescued up-regulation of Btk protein in xid splenic B cells. These combined results suggest that certain receptor signals mediated by Btk regulate the level of expression of Btk protein in responding B lymphocytes to potentiate signal transduction. Dynamic regulation of Btk protein dosage is an additional mechanism to modulate B lymphocyte immune functions.
AB - Mutation of Bruton's tyrosine kinase (Btk) causes human X-linked agammaglobulinemia and murine X-linked immunodeficiency syndrome (xid). Quantitative aspects of B lymphocyte development and function have been demonstrated to depend on Btk level in vivo by using a murine transgenic model system. A sensitive intracellular immunofluorescent assay was developed to measure Btk protein on a per cell basis to test the hypothesis that its dosage is dynamically regulated during B cell development or functional responses. Marrow-derived hematopoietic stem cells, common lymphoid progenitor cells, and developing B and myeloid lineages expressed Btk protein at comparable levels. Resting peripheral B lineage cells had a significantly lower amount of Btk than marrow-derived cells in both wild-type and xid mice. Activation of the B cell antigen receptor up-regulated Btk protein level 10- fold within several hours by a phosphatidylinositol 3-kinase-dependent, post- transcriptional mechanism. In contrast, the protein level of Btk R2BC in activated B lymphocytes from xid mice remained low. Bypass of the antigen receptor signaling pathways by treatment of cells with phorbol myristic acid and ionomycin rescued up-regulation of Btk protein in xid splenic B cells. These combined results suggest that certain receptor signals mediated by Btk regulate the level of expression of Btk protein in responding B lymphocytes to potentiate signal transduction. Dynamic regulation of Btk protein dosage is an additional mechanism to modulate B lymphocyte immune functions.
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U2 - 10.1073/pnas.050583597
DO - 10.1073/pnas.050583597
M3 - Article
C2 - 10688914
AN - SCOPUS:0034646471
SN - 0027-8424
VL - 97
SP - 2737
EP - 2742
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 6
ER -