Bcl-xL and E1B-19K proteins inhibit p53-induced irreversible growth arrest and senescence by preventing reactive oxygen species-dependent p38 activation
Bcl-xL and E1B-19K proteins inhibit p53-induced irreversible growth arrest and senescence by preventing reactive oxygen species-dependent p38 activation
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DOI：
10.1074/jbc.m305015200
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发表时间：
2004-04-23
影响因子：
4.8
通讯作者：
Shin, DY
中科院分区：
文献类型：
--
作者：
Jung, MS;Jin, DH;Shin, DY
在这项研究中，我们描述了抗凋亡Bcl-2家族蛋白的新功能。发现Bcl-x（L）和E1 B-19 K抑制p53诱导的不可逆生长停滞和衰老，但不抑制瞬时生长停滞，这意味着Bcl-x（L）和E1 B-19 K特异性地参与衰老而不参与生长停滞。我们提供了一些证据表明Bcl-x（L）和E1 B-19 K阻止活性氧（ROS）产生的功能对于抑制衰老诱导是重要的。首先，我们发现ROS在p53诱导的衰老过程中增加。此外，Bcl-x（L）和E1 B-19 K抑制这种p53诱导的ROS产生。第二，抗氧化剂阻止p53诱导衰老和ROS，但不能阻止衰老表型的持续。第三，外源ROS的加入抑制了Bcl-x（L）和E1 B-19 K的抗衰老作用。这些结果表明Bcl-x（L）和E1 B-19 K通过阻止ROS的产生来抑制衰老诱导。此外，发现p38激酶在p53诱导的衰老过程中被激活，但在表达Bcl-x（L）或E1 B-19 K的细胞中或在用抗氧化剂处理的细胞中不被激活。Considerate，一种p38激酶的化学抑制剂，SB 203580，被发现抑制p53诱导的衰老，但只有当处理之前的细胞衰老的承诺，这意味着p38激酶是必要的衰老诱导。因此，Bcl-x（L）和E1 B-19 K通过阻止ROS产生来抑制p53诱导的衰老，这反过来导致p38激酶的激活。这些结果还表明，Bcl-2的致癌潜力是由于其抑制衰老以及凋亡的能力。
In this study, we describe novel functions of the antiapoptotic Bcl-2 family proteins. Bcl-x(L) and E1B-19K were found to inhibit p53-induced irreversible growth arrest and senescence, but not to inhibit transient growth arrest, implying that Bcl-x(L) and E1B-19K are specifically involved in senescence without participating in growth arrest. We provide several lines of evidences showing that the functions of Bcl-x(L) and E1B-19K to prevent generation of reactive oxygen species (ROS) are important to inhibit senescence induction. First, we found that that ROS are increased during p53-induced senescence. Moreover, Bcl-x(L) and E1B-19K inhibit this p53-induced ROS generation. Second, antioxidants prevent the induction of senescence and ROS by p53, but not the persistence of the senescence phenotype. Third, the anti-senescence functions of Bcl-x(L) and E1B-19K were suppressed by adding exogenous ROS. These results suggest that Bcl-x(L) and E1B-19K inhibit senescence induction by preventing ROS generation. Furthermore, p38 kinase was found to be activated during p53-induced senescence, but not in cells expressing Bcl-x(L) or E1B-19K, or in cells treated with anti-oxidants. Consistently, a chemical inhibitor of p38 kinase, SB203580, was found to inhibit p53-induced senescence, but only when treated before the cellular commitment to senescence, implying that p38 kinase is necessary for senescence induction. Therefore, Bcl-x(L) and E1B-19K inhibit p53-induced senescence by preventing ROS generation, which in turn leads to the activation of p38 kinase. These results also suggest that the oncogenic potential of Bcl-2 is due to its ability to inhibit senescence as well as apoptosis.