CD45により制御されるB細胞核内因子の解析

我们一直试图通过从未成熟和成熟的B细胞系中克隆CD45来阐明CD45在B细胞抗原受体(BCR)介导的信号转导中的作用。我们以前报道过CD45以一种不同的方式调节各种细胞过程，这取决于B细胞的成熟阶段。在未成熟的B细胞系WEHI-231中，CD45负调控BCR介导的生长停滞和凋亡。相反，在成熟的B细胞系BAL-17中，BCR诱导的生长停滞是由CD45正向和关键地调节的。为了更准确地定义CD45在未成熟和成熟B细胞中所控制的信号转导通路，我们重点研究了MAP激酶通路。结果表明，在未成熟B细胞系WEHI-231中，CD45正向调节ERK活性，负向调节JNK和p38活性；而在成熟B细胞系BAL-17中，CD45负向调节ERK活性，正向调节JNK和p38活性。因此，CD45以离散的方式参与MAP激酶通路不同成员的调节，其在未成熟B细胞中的调节模式与在成熟B细胞中的调节模式相反。此外，JNK和p38的激活与生长停滞程度的增加密切相关。我们正在使用显性阴性形式的MKK4(JNK的激活剂)和p38的抑制物(SB203580)来研究JNK和p38对生长停滞的直接贡献。

We have been trying to elucidate the role of CD45 in B cell antigen receptor (BCR)-mediated signal transduction by using CD45-negative clones from immature and mature B cell lines. We previously reported that CD45 regulates various cellular processes in a distinct manner, depending on maturational stages of B cells. In an immature B cell line WEHI-231, BCR-mediated growth arrest and apoptosis are negatively regulated by CD45. In contrast, in a mature B cell line BAL-17, BCR-induced growth arrest is regulated positively and crucially by CD45.To define more precisely the signal transduction pathways governed by CD45 in immature and mature B cells, we focused on MAP kinase pathways. The results demonstrated that in the immature B cell line WEHI-231, ERK kinase activity is regulated positively and JNK and p38 kinase activities are negatively regulated by CD45, whereas in the mature B cell line BAL-17, CD45 regulates ERK kinase negatively and JNK and p38 kinase activities positively. Thus, CD45 is concerned with regulation of different members of MAP kinase pathways in a discrete manner, and its regulatory mode in immature B cells is opposite to that in mature B cells. Furthermore, there was a close correlation between activation of JNK and p38 and an increase in the degree of growth arrest. We are in the process of examining the direct contribution of JNK and p38 to the growth arrest by using dominant negative form of MKK4 (an activator of JNK) and a p38 inhibitor (SB203580).