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首页> 外文期刊>Journal of Cellular Physiology >Rapamycin attenuates BAFF‐extended proliferation and survival via disruption of mTORC1/2 signaling in normal and neoplastic B‐lymphoid cells
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Rapamycin attenuates BAFF‐extended proliferation and survival via disruption of mTORC1/2 signaling in normal and neoplastic B‐lymphoid cells

机译：雷帕霉素变弱高飞球的一击扩展扩散通过mTORC1/2中断信号和生存在正常和肿瘤B淋巴细胞

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摘要

B cell activating factor from the TNF family (BAFF) stimulates B‐cell proliferation and survival, but excessive BAFF promotes the development of aggressive B cells leading to malignant and autoimmune diseases. Recently, we have reported that rapamycin, a macrocyclic lactone, attenuates human soluble BAFF (hsBAFF)‐stimulated B‐cell proliferation/survival by suppressing mTOR‐mediated PP2A‐Erk1/2 signaling pathway. Here, we show that the inhibitory effect of rapamycin on hsBAFF‐promoted B cell proliferation/survival is also related to blocking hsBAFF‐stimulated phosphorylation of Akt, S6K1, and 4E‐BP1, as well as expression of survivin in normal and B‐lymphoid (Raji and Daudi) cells. It appeared that both mTORC1 and mTORC2 were involved in the inhibitory activity of rapamycin, as silencing raptor or rictor enhanced rapamycin's suppression of hsBAFF‐induced survivin expression and proliferation/viability in B cells. Also, PP242, an mTORC1/2 kinase inhibitor, repressed survivin expression, and cell proliferation/viability more potently than rapamycin (mTORC1 inhibitor) in B cells in response to hsBAFF. Of interest, ectopic expression of constitutively active Akt (myr‐Akt) or constitutively active S6K1 (S6K1‐ca), or downregulation of 4E‐BP1 conferred resistance to rapamycin's attenuation of hsBAFF‐induced survivin expression and B‐cell proliferation/viability, whereas overexpression of dominant negative Akt (dn‐Akt) or constitutively hypophosphorylated 4E‐BP1 (4EBP1‐5A), or downregulation of S6K1, or co‐treatment with Akt inhibitor potentiated the inhibitory effects of rapamycin. The findings indicate that rapamycin attenuates excessive hsBAFF‐induced cell proliferation/survival via blocking mTORC1/2 signaling in normal and neoplastic B‐lymphoid cells. Our data underscore that rapamycin may be a potential agent for preventing excessive BAFF‐evoked aggressive B‐cell malignancies and autoimmune diseases.
机译：B细胞激活因子TNF家族的(金属)刺激B细胞增殖和但是过度的生存,促进金属激进的B细胞导致的发展恶性肿瘤和自身免疫性疾病。有报道称,雷帕霉素,大环的吗内酯,人类可溶性金属变弱(hsBAFF)量刺激B细胞增殖/生存通过抑制mTOR介导PP2A Erk1/2应承担的信号通路。抑制作用的雷帕霉素hsBAFF提升B细胞增殖/生存也有关阻塞hsBAFF刺激的磷酸化Akt、S6K1和4 e高BP1的表达生存素在正常和B淋巴(Raji和Daudi)细胞。mTORC2参与抑制活动雷帕霉素,沉默猛禽或rictor增强的雷帕霉素抑制的hsBAFF存活素诱导表达和扩散/ B细胞的可行性。一个mTORC1/2激酶抑制剂,压抑的生存素表达和细胞增殖/可行性有说服力地比雷帕霉素B (mTORC1抑制剂)hsBAFF细胞反应。表达持续活跃的一种蛋白激酶(myr Akt应承担的)或者持续活跃S6K1(地理S6K1 ca),或downregulation 4 e BP1授予抵抗雷帕霉素的衰减hsBAFF诱导生存素表达和B细胞扩散/可行性,而过度占主导地位的消极的一种蛋白激酶(dn公/ Akt)或既定的hypophosphorylated 4 e BP15 (4 ebp1所致),S6K1,差别或对这些或公司待遇与Akt抑制剂疗效雷帕霉素抑制的影响。表明,雷帕霉素减弱过度hsBAFF通过诱导细胞增殖/生存阻塞mTORC1/2信号在正常和异常肿瘤B淋巴细胞。雷帕霉素可能潜在的代理防止过度金属诱发攻击性B细胞恶性肿瘤和自身免疫性疾病。

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