MAPK regulate p53-dependent cell death induced by benzo[a]pyrene: Involvement of p53 phosphorylation and acetylation
MAPK regulate p53-dependent cell death induced by benzo[a]pyrene: Involvement of p53 phosphorylation and acetylation
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DOI：
10.1016/j.tox.2008.02.017
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发表时间：
2008-05-21
期刊：
影响因子：
4.5
通讯作者：
Yang, M. S.
中科院分区：
文献类型：
--
作者：
Lin, T.;Mak, N. K.;Yang, M. S.
苯并[a]芘（BaP）是一种具有潜在遗传毒性和细胞毒性的环境污染物。先前的研究表明，HepG（2）细胞暴露于BaP导致坏死性细胞死亡[Lin，T.，Yang，M. S.，2007年b。苯并[a]芘诱导的HepG 2细胞死亡依赖于PARP-1激活和NAD耗竭。毒理学245，147-153]。在本研究中，与这种反应相关的信号通路进行了研究。BaP诱导HepG 2细胞中p53的积累和激活，这发生早在暴露后12 h。p53的活化通过其丝氨酸15（Ser 15）的磷酸化和赖氨酸382（Lys 382）的乙酰化来证明。化学抑制和siRNA介导的p53表达的敲低抑制了其磷酸化以及细胞死亡。BaP还激活p38 MAPK和ERK，但不激活JNK。SB 203580和PD 98059分别是p38 MAPK和ERK的特异性抑制剂，抑制p53在Ser 15的磷酸化，但p53的积累仅适度减少。p53在赖氨酸382的乙酰化不受这些抑制剂的影响，表明乙酰化稳定p53在DNA损伤的反应。SB 203580和PD 98059防止下游能量衰竭和BaP诱导的细胞死亡。用针对p38 MAPK的两种同种型p38 α和p38 β的siRNA获得了类似的结果。选择性DNA-PK和ATM/ATR抑制剂Wortmannin可抑制p53磷酸化，表明BaP诱导p53磷酸化的多途径参与。总之，目前的研究表明，MAPK和p53激活都需要BaP诱导的坏死细胞死亡。该结果也为研究p53和p38 MAPK在细胞坏死过程中的相互调节提供了一种新的模型。(C)2008爱思唯尔爱尔兰有限公司保留所有权利。
Benzo[a]pyrene (BaP) is a potentially genotoxic and cytotoxic environmental pollutant. Previous studies showed that exposure of HepG(2) cells to BaP causes necrotic cell death [Lin, T., Yang, M.S., 2007b. Cell death induced by benzo[a]pyrene in the HepG2 cells is dependent on PARP-1 activation and NAD depletion. Toxicology 245, 147-153]. In the present study, the signaling pathways associated with this response was studied. BaP induced accumulation and activation of p53 in HepG2 cells, which occurred as early as 12 h after exposure. Activation of p53 was evidenced by its phosphorylation at serine 15 (Ser15) and acetylation at lysine 382 (Lys382). Chemical inhibition and siRNA-mediated knockdown of p53 expression suppressed its phosphorylation as well as cell death. BaP also activated p38 MAPK and ERK, but not JNK, at 6 h after exposure. SB203580 and PD98059, specific inhibitors of p38 MAPK and ERK, respectively, suppressed phosphorylation of p53 at Ser15, but the accumulation of p53 was only moderately reduced. Acetylation of p53 at Lys 382 was not affected by these inhibitors, suggesting that acetylation stabilizes p53 in response to DNA damage. SB203580 and PD98059 prevented downstream energy failure and BaP-induced cell death. Similar results were obtained with siRNA against two isoforms of p38 MAPK, p38 alpha and p38 beta. Wortmannin, selective inhibitor of DNA-PK and ATM/ATR, abolished p53 phosphorylation, indicating an involvement of multiple pathways of p53 phosphorylation upon exposure to BaP. In summary, the current study demonstrated that both MAPK and p53 activation are required for BaP-induced necrotic cell death. The results also provide a novel model for studying the regulation between p53 and p38 MAPK in the progression of cellular necrosis. (C) 2008 Elsevier Ireland Ltd. All rights reserved.