Phosphatidylinositol 3-kinase and NF-κB/Rel are at the divergence of CD40-mediated proliferation and survival pathways
Phosphatidylinositol 3-kinase and NF-κB/Rel are at the divergence of CD40-mediated proliferation and survival pathways
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DOI：
10.4049/jimmunol.165.7.3860
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发表时间：
2000-10-01
影响因子：
4.4
通讯作者：
Liou, HC
中科院分区：
文献类型：
--
作者：
Andjelic, S;Hsia, C;Liou, HC
CD40 受体连接会对激活的 B 细胞的命运产生几个关键结果，包括增殖和存活。尽管已鉴定出 CD40 通路中的多种信号分子，但它们在调节增殖和维持细胞活力中的具体作用仍不清楚。在本报告中，我们证明磷脂酰肌醇 3 激酶 (PI-3K) 和 NF-kappa B/Rel 转录因子的激活对于 CD40 介导的增殖至关重要。此外，我们的数据表明 PI-3K 对于 CD40 介导的 NF-kappa B/Rel 激活是不可或缺的。这是通过激活 AKT 和降解 I kappa B α 来实现的。此外，我们表明 PI-3K 活性对于细胞周期蛋白依赖性激酶抑制剂 p27(kip) 的降解是必需的。因此，这两个事件构成了 PI-3K 控制细胞增殖的机制。与增殖的绝对需要 PI-3K 和 NF-κ B/Rel 相比，这些信号分子仅部分负责 CD40 介导的存活，因为阻断 PI-3K 活性不会导致抗 CD40 处理的细胞凋亡。然而，PI3K/NF-kappa B 途径仍然是 CD40 诱导的 Bcl-X 基因表达所必需的。综上所述，我们的数据表明多种生存途径是通过该受体触发的，而 NF-kappa B/Rel 和 PI-3K 对于 CD40 诱导的增殖至关重要。
CD40 receptor ligation evokes several crucial outcomes for the fate of an activated B cell, including proliferation and survival. Although multiple signaling molecules in the CD40 pathways have been identified, their specific roles in regulating proliferation and maintaining cell viability are still obscure. In this report, we demonstrate that the activation of both phosphatidylinositol 3-kinase (PI-3K) and NF-kappa B/Rel transcription factors is crucial for CD40-mediated proliferation. Furthermore, our data indicate that PI-3K is indispensable for CD40-mediated NF-kappa B/Rel activation. This is achieved via activation of AKT and the degradation of I kappa B alpha. Furthermore, we show that PI-3K activity is necessary for the degradation of cyclin-dependent kinase inhibitor p27(kip). Therefore, both of these events comprise the mechanism by which PI-3K controls cell proliferation. In contrast to the absolute requirement of PI-3K and NF-kappa B/Rel for proliferation, these signaling molecules are only partially responsible for CD40-mediated survival, as blocking of PI-3K activity did not lead to apoptosis of anti-CD40-treated cells. However, the PI3K/NF-kappa B pathway is still required for CD40-induced Bcl-X gene expression. Taken together, our data indicate that multiple survival pathways are triggered via this receptor, whereas NF-kappa B/Rel and PI-3K are crucial for CD40-induced proliferation.