Increased sensitivity of CLL-derived lymphocytes to apoptotic death activation by the proteasome-specific inhibitor lactacystin
Increased sensitivity of CLL-derived lymphocytes to apoptotic death activation by the proteasome-specific inhibitor lactacystin
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DOI：
10.1046/j.1365-2141.1999.01388.x
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发表时间：
1999-06-01
影响因子：
6.5
通讯作者：
Delic, J
中科院分区：
文献类型：
--
作者：
Masdehors, P;Omura, S;Delic, J
泛素蛋白酶体依赖的蛋白质加工似乎是控制辐射诱导的人淋巴细胞凋亡的重要组成部分。与照射后主要表现为高凋亡值的正常人淋巴细胞相比，慢性淋巴细胞性白血病(CLL)患者的这种控制性改变。但在某些情况下，没有观察到敏感性。有趣的是，lactacystin在辐射抵抗和敏感的CLL细胞中都激活了凋亡途径，剂量对需要显著更高浓度的正常细胞没有影响。因此，某些CLL细胞对辐射启动的凋亡的抵抗与观察到的对lactacystin的敏感性增加无关。照射或lactacystin CLL细胞处理后，转录因子NF-kappa B的核水平或胞浆I-kappa Bα水平均未发生改变，提示参与细胞死亡控制的其他因子的活性可能通过蛋白酶体抑制而改变。这些结果有力地表明泛素系统在CLL淋巴细胞的凋亡细胞死亡控制中起着重要的作用，抑制蛋白酶体-泛素依赖的处理可能是正常和恶性淋巴细胞之间的区别凋亡刺激，因此可能在这一特定的人类病理学中使用。
Ubiquitin-proteasome-dependent protein processing appears to be an essential component in the control of radiation-induced apoptosis in human lymphocytes. This control is altered in chronic lymphocytic leukaemia (CLL), compared to that of normal human lymphocytes which mainly showed high apoptotic values after irradiation. but in some cases no sensitivity was observed. Interestingly, lactacystin activated the apoptotic pathway in both radioresistant and sensitive CLL cells, at doses which had no effect in normal cells where significantly higher concentrations were required. Therefore the resistance of some CLL cells to apoptosis initiation by radiation does not correlate to observed increased sensitivity to lactacystin. The nuclear level of the transcription factor NF-kappa B or the cytoplasmic level of I kappa B alpha remained unaltered upon irradiation or lactacystin CLL cells treatment, suggesting that the activity of the other factors involved in apoptotic death control were altered through proteasomal inhibition. These results strongly suggest an essential role of the ubiquitin system in apoptotic cell death control in CLL lymphocytes, The inhibition of proteasome-ubiquitin-dependent processing could be a discriminatory apoptotic stimulus between normal versus malignant lymphocytes and therefore might potentially be of use in this specific human pathology.