BAFF activates Erk1/2 promoting cell proliferation and survival by Ca2+-CaMKII-dependent inhibition of PP2A in normal and neoplastic B-lymphoid cells.
BAFF activates Erk1/2 promoting cell proliferation and survival by Ca2+-CaMKII-dependent inhibition of PP2A in normal and neoplastic B-lymphoid cells.
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DOI：
10.1016/j.bcp.2013.11.006
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发表时间：
2014-01-15
影响因子：
5.8
通讯作者：
Chen, Long
中科院分区：
文献类型：
--
作者：
Liang, Dingfang;Zeng, Qingyu;Xu, Zhigang;Zhang, Hai;Gui, Lin;Xu, Chong;Chen, Sujuan;Zhang, Shuangquan;Huang, Shile;Chen, Long
B细胞活化因子（BAFF）不仅参与正常B细胞的生理过程，而且参与恶性肿瘤和自身免疫性疾病相关的侵袭性B细胞的病理生理过程。然而，过量的BAFF如何促进侵袭性B细胞增殖和存活尚不清楚。在这里，我们表明，过量的人可溶性BAFF（hsBAFF）增强细胞增殖和生存在正常和B淋巴（Raji）细胞，这是与抑制PP 2A，导致Erk 1/2的激活。这得到了以下发现的支持：用U 0126或PD 98059预处理、显性负性MKK 1的表达或PP 2A的过表达阻止了hsBAFF诱导的Erk 1/2活化和细胞增殖/活力。hsBAFF介导的PP 2A-Erk 1/2途径和B细胞增殖/活力似乎是Ca 2+依赖性的，因为BAPTA/AM、EGTA或2-APB预处理显著减弱了这些事件。此外，我们发现用KN 93抑制CaMKII或沉默CaMKII也减弱hsBAFF介导的PP 2A-Erk 1/2信号传导和B细胞增殖/活力。结果表明，BAFF激活Erk 1/2，部分通过Ca 2 +-CaMK II依赖性抑制PP 2A，增加正常和肿瘤性B淋巴细胞的细胞增殖/活力。我们的数据表明，抑制剂的CaMKII和Erk 1/2，激活PP 2A或操纵细胞内的Ca 2+可用于预防过度BAFF诱导的侵袭性B细胞恶性肿瘤和自身免疫性疾病。
B-cell activating factor (BAFF) is involved in not only the physiology of normal B cells, but also the pathophysiology of aggressive B cells related to malignant and autoimmune diseases. However, how excessive BAFF promotes aggressive B-cell proliferation and survival is not well understood. Here we show that excessive human soluble BAFF (hsBAFF) enhanced cell proliferation and survival in normal and B-lymphoid (Raji) cells, which was associated with suppression of PP2A, resulting in activation of Erk1/2. This is supported by the findings that pretreatment with U0126 or PD98059, expression of dominant negative MKK1, or overexpression of PP2A prevented hsBAFF-induced activation of Erk1/2 and cell proliferation/viability in the cells. It appears that hsBAFF-mediated PP2A-Erk1/2 pathway and B-cell proliferation/viability was Ca2+-dependent, as pretreatment with BAPTA/AM, EGTA or 2-APB significantly attenuated these events. Furthermore, we found that inhibiting CaMKII with KN93 or silencing CaMKII also attenuated hsBAFF-mediated PP2A-Erk1/2 signaling and B-cell proliferation/viability. The results indicate that BAFF activates Erk1/2, in part through Ca2+-CaMKII-dependent inhibition of PP2A, increasing cell proliferation/viability in normal and neoplastic B-lymphoid cells. Our data suggest that inhibitors of CaMKII and Erk1/2, activator of PP2A or manipulation of intracellular Ca2+ may be exploited for prevention of excessive BAFF-induced aggressive B-cell malignancies and autoimmune diseases.
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DOI：
10.4049/jimmunol.1200143
发表时间：
2012-04-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Crispín JC;Apostolidis SA;Rosetti F;Keszei M;Wang N;Terhorst C;Mayadas TN;Tsokos GC
通讯作者：
Tsokos GC
影响因子：
30.5
作者：
Doreau, Agnes;Belot, Alexandre;Bonnefoy-Berard, Nathalie
通讯作者：
Bonnefoy-Berard, Nathalie
影响因子：
5.4
作者：
Henley, Thomas;Kovesdi, Dorottya;Turner, Martin
通讯作者：
Turner, Martin
CaMKII 参与镉激活 MAPK 和 mTOR 通路，导致神经元细胞死亡
影响因子：
4.7
作者：
Chen S;Xu Y;Xu B;Guo M;Zhang Z;Liu L;Ma H;Chen Z;Luo Y;Huang S;Chen L
通讯作者：
Chen L
影响因子：
15.9
作者：
Groom, J;Kalled, SL;Mackay, F
通讯作者：
Mackay, F