title: B cell receptor-ERK1/2 signal cancels PAX5-dependent repression of BLIMP1 through PAX5 phosphorylation: a mechanism of antigen-triggering plasma cell differentiation.
abstract: Plasma cell differentiation is initiated by Ag stimulation of BCR. Until BCR stimulation, B lymphocyte-induced maturation protein 1 (BLIMP1), a master regulator of plasma cell differentiation, is suppressed by PAX5, which is a key transcriptional repressor for maintaining B cell identity. After BCR stimulation, upregulation of BLIMP1 and subsequent suppression of PAX5 by BLIMP1 are observed and thought to be the trigger of plasma cell differentiation; however, the trigger that derepresses BLIMP1 expression is yet to be revealed. In this study, we demonstrated PAX5 phosphorylation by ERK1/2, the main component of the BCR signal. Transcriptional repression on BLIMP1 promoter by PAX5 was canceled by PAX5 phosphorylation. BCR stimulation induced ERK1/2 activation, phosphorylation of endogenous PAX5, and upregulation of BLIMP1 mRNA expression in B cells. These phenomena were inhibited by MEK1 inhibitor or the phosphorylation-defective mutation of PAX5. These data imply that PAX5 phosphorylation by the BCR signal is the initial event in plasma cell differentiation.
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, Nagoya University, Nagoya, 466-8550, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Yasuda
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Hayakawa
authors.forename: Shingo
authors.initials: S
authors.lastname: Kurahashi
authors.forename: Keiki
authors.initials: K
authors.lastname: Sugimoto
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Minami
authors.forename: Akihiro
authors.initials: A
authors.lastname: Tomita
authors.forename: Tomoki
authors.initials: T
authors.lastname: Naoe
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D024202:Electrophoretic Mobility Shift Assay; D005455:Fluorescent Antibody Technique; D006801:Humans; D015151:Immunoblotting; D008213:Lymphocyte Activation / Q000276:immunology; D008223:Lymphoma / Q000276:immunology / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D051757:PAX5 Transcription Factor / Q000276:immunology / Q000378:metabolism*; D010766:Phosphorylation; D010950:Plasma Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D000074462:Positive Regulatory Domain I-Binding Factor 1; D060888:Real-Time Polymerase Chain Reaction; D011947:Receptors, Antigen, B-Cell / Q000276:immunology / Q000378:metabolism*; D012097:Repressor Proteins / Q000276:immunology / Q000378:metabolism*; D014162:Transfection
chemical_list: D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human; D011947:Receptors, Antigen, B-Cell; D012097:Repressor Proteins; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1