Induction of p38δ Expression Plays an Essential Role in Oncogenic ras-Induced Senescence
Induction of p38δ Expression Plays an Essential Role in Oncogenic ras-Induced Senescence
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DOI：
10.1128/mcb.00784-13
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发表时间：
2013-10-01
影响因子：
5.3
通讯作者：
Sun, Peiqing
中科院分区：
文献类型：
--
作者：
Kwong, Jinny;Chen, Michelle;Sun, Peiqing
癌基因诱导的衰老是一种稳定的增殖停滞，作为一种肿瘤抑制防御机制。p38丝裂原活化蛋白激酶（MAPK）与癌基因诱导的衰老和肿瘤抑制有关。然而，四种p38亚型中的每一种在癌基因诱导的衰老中的具体作用尚未完全了解。在这里，我们证明，p38 δ介导癌基因诱导的衰老通过p53和p16（INK 4A）的独立机制。相反，有证据表明p38 delta与DNA损伤途径之间存在联系。此外，我们还发现了一种新的机制，在衰老过程中增强p38 δ的表达。在该机制中，致癌ras诱导Raf-1-MEK-细胞外信号调节激酶（ERK）途径，其反过来激活与p38 δ启动子结合的AP-1和Ets转录因子，导致p38 δ转录增加。这些发现表明，致癌ras对p38 delta衰老功能的诱导是通过2种机制实现的，即Raf-1-MEK-ERK-AP-1/Ets途径的转录激活，这增加了p38 delta蛋白的细胞浓度，以及MKK 3/6的翻译后修饰，这刺激了p38 delta的酶活性。此外，这些研究确定了AP-1和Ets转录因子作为衰老诱导途径中的新信号传导组分。
Oncogene-induced senescence is a stable proliferative arrest that serves as a tumor-suppressing defense mechanism. p38 mitogen-activated protein kinase (MAPK) has been implicated in oncogene-induced senescence and tumor suppression. However, the specific role of each of the four p38 isoforms in oncogene-induced senescence is not fully understood. Here, we demonstrate that p38 delta mediates oncogene-induced senescence through a p53- and p16(INK4A)-independent mechanism. Instead, evidence suggests a link between p38 delta and the DNA damage pathways. Moreover, we have discovered a novel mechanism that enhances the expression of p38 delta during senescence. In this mechanism, oncogenic ras induces the Raf-1-MEK-extracellular signal-regulated kinase (ERK) pathway, which, in turn, activates the AP-1 and Ets transcription factors that are bound to the p38 delta promoter, leading to increased transcription of p38 delta. These findings indicate that induction of the prosenescent function of p38 delta by oncogenic ras is achieved through 2 mechanisms, transcriptional activation by the Raf-1-MEK-ERK-AP-1/Ets pathway, which increases the cellular concentration of the p38 delta protein, and posttranslational modification by MKK3/6, which stimulates the enzymatic activity of p38 delta. In addition, these studies identify the AP-1 and Ets transcription factors as novel signaling components in the senescence-inducing pathway.