The apoptosis-associated gamma-ray response of BCL-X(L) depends on normal p53 function.
The apoptosis-associated gamma-ray response of BCL-X(L) depends on normal p53 function.
复制标题
BCL-X(L) 的凋亡相关伽马射线反应取决于正常的 p53 功能。
作者：
Q. Zhan;I. Alamo;K. Yu;L. Boise;B. Cherney;G. Tosato;P. O'Connor;A. Fornace
我们研究了DNA损伤对BCL-2家族成员BCL-X表达的影响。发现BCL-X mRNA水平在将人细胞暴露于电离辐射（IR）后增加。与BCL-2家族的另一个成员BAX和p53调节基因一样，BCL-X（L）蛋白的诱导依赖于正常的p53功能，并且需要细胞具有凋亡易感表型。BCL-X（L）的诱导是快速、短暂和剂量依赖性的。mRNA水平在照射后4 h达到峰值，24 h恢复到基线水平。与转录水平增加一致，在IR触发凋亡的野生型p53细胞中也观察到Bcl-X（L）蛋白水平增加。此外，对具有已知凋亡反应的人类细胞中BCL-X（L）mRNA基础水平的调查显示，细胞中BCL-X（L）mRNA的低基础水平与细胞经历IR诱导的凋亡的强能力高度相关。另一方面，高水平的基础BCL-X（L）与细胞对IR诱导的凋亡的抗性相关，而与p53状态无关。这些结果表明，BCL-2和BCL-X（L）对DNA损伤处理的反应不同，即使它们都能够保护细胞免受p53介导的凋亡;在具有野生型p53和对IR诱导的凋亡敏感的人细胞中，BCL-2的下调沿着BCL-X（L）被IR上调。我们推测BCL-X（L）蛋白增加的生理功能可能会限制BAX效应的严重程度和长度，以维持适当的凋亡阈值并完成由p53激活的细胞周期阻滞。
We have investigated the effect of DNA damage on the expression of BCL-X, a member of the BCL-2 family. BCL-X mRNA levels were found to increase upon exposure human cells to ionizing radiation (IR). The Bcl-X(L) protein, but not Bcl-X(S), was identified to be induced by IR. Like BAX, another member of the BCL-2 family and a p53-regulated gene, the induction of BCL-X(L) was dependent on normal p53 function and required that cells have an apoptosis-susceptible phenotype. The induction of BCL-X(L) was rapid, transient and dose-dependent. The mRNA level peaked at 4 h and returned to baseline by 24 h post-irradiation. In agreement with the increased transcript level, Bcl-X(L) protein level was also observed to increase in cells with wild-type p53 where IR triggered apoptosis. In addition, a survey of the BCL-X(L) mRNA basal levels in human cells with known apoptotic responses showed that low basal levels of BCL-X(L) mRNA in cells were highly correlated with a strong ability of cells to undergo IR-induced apoptosis. On the other hand, high levels of basal BCL-X(L) were correlated with the resistance of cells to IR-induced apoptosis regardless of p53 status. These results indicate that BCL-2 and BCL-X(L) behave differently in response to DNA damage treatment even though they both are able to protect cells from p53-mediated apoptosis; along with down-regulation of BCL-2, BCL-X(L) was up-regulated by IR in human cells with wild-type p53 and susceptibility to IR-induced apoptosis. We speculate that the physiological function of increased BCL-X(L) protein would be expected to probably limit the severity and length of BAX effect in order to maintain a proper threshold for apoptosis and to complete cell cycle arrest activated by p53.