Resveratrol-induced activation of p53 and apoptosis is mediated by extracellular-signal-regulated protein kinases and p38 kinase.
Resveratrol-induced activation of p53 and apoptosis is mediated by extracellular-signal-regulated protein kinases and p38 kinase.
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发表时间：
2001-02
期刊：
影响因子：
11.2
通讯作者：
Q. She;A. Bode;Weiya Ma;N. Chen;Z. Dong
中科院分区：
文献类型：
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作者：
Q. She;A. Bode;Weiya Ma;N. Chen;Z. Dong
白藜芦醇是一种植物抗毒素，存在于葡萄、浆果和花生中，是最有前途的癌症预防剂之一。我们以前的研究表明，白藜芦醇的抗肿瘤活性是通过p53介导的细胞凋亡发生的。在这项研究中，我们已经阐明了潜在的白藜芦醇诱导的p53激活和诱导细胞凋亡的信号成分。我们发现，在小鼠JB 6表皮细胞系中，白藜芦醇激活细胞外信号调节蛋白激酶（ERK），c-Jun NH 2-末端激酶（JNKs）和p38激酶，并诱导p53的丝氨酸15磷酸化。ERK 2或p38激酶或其各自的抑制剂PD 98059或SB 202190的显性负突变体的稳定表达抑制了p53在丝氨酸15处的磷酸化。相反，显性失活突变体JNKI的过度表达对磷酸化没有影响。最重要的是，ERK和p38激酶在白藜芦醇处理后与p53形成复合物。引人注目的是，白藜芦醇激活的ERK和p38激酶，而不是JNK，在体外磷酸化p53的丝氨酸15。此外，用PD 98059或SB 202190或ERK 2或p38激酶的显性负突变体的稳定表达预处理细胞损害白藜芦醇诱导的p53依赖性转录活性和凋亡，而组成性活性MEK 1增加p53的转录活性。这些数据有力地表明，ERK和p38激酶介导白藜芦醇诱导的p53激活和细胞凋亡，通过磷酸化p53在丝氨酸15。
Resveratrol, a phytoalexin found in grapes, berries, and peanuts, is one of the most promising agents for cancer prevention. Our previous study showed that the antitumor activity of resveratrol occurs through p53-mediated apoptosis. In this study, we have elucidated the potential signaling components underlying resveratrol-induced p53 activation and induction of apoptosis. We found that in a mouse JB6 epidermal cell line, resveratrol activated extracellular-signal-regulated protein kinases (ERKs), c-Jun NH2-terminal kinases (JNKs), and p38 kinase and induced serine 15 phosphorylation of p53. Stable expression of a dominant negative mutant of ERK2 or p38 kinase or their respective inhibitor, PD98059 or SB202190, repressed the phosphorylation of p53 at serine 15. In contrast, overexpression of a dominant negative mutant of JNKI had no effect on the phosphorylation. Most importantly, ERKs and p38 kinase formed a complex with p53 after treatment with resveratrol. Strikingly, resveratrol-activated ERKs and p38 kinase, but not JNKs, phosphorylated p53 at serine 15 in vitro. Furthermore, pretreatment of the cells with PD98059 or SB202190 or stable expression of a dominant negative mutant of ERK2 or p38 kinase impaired resveratrol-induced p53-dependent transcriptional activity and apoptosis, whereas constitutively active MEK1 increased the transcriptional activity of p53. These data strongly suggest that both ERKs and p38 kinase mediate resveratrol-induced activation of p53 and apoptosis through phosphorylation of p53 at serine 15.