A critical role of PI-3K/Akt/JNKs pathway in benzo[a]pyrene diol-epoxide (B[a]PDE)-induced AP-1 transactivation in mouse epidermal Cl41 cells
A critical role of PI-3K/Akt/JNKs pathway in benzo[a]pyrene diol-epoxide (B[a]PDE)-induced AP-1 transactivation in mouse epidermal Cl41 cells
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DOI：
10.1038/sj.onc.1207501
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发表时间：
2004-05-13
期刊：
影响因子：
8
通讯作者：
Huang, C
中科院分区：
文献类型：
--
作者：
Li, JX;Tang, MS;Huang, C
小鼠皮肤致瘤性研究表明，苯并[a]-芘-7,8-二醇-9,10-环氧化物（B[a]PDE）作为肿瘤引发剂和促进剂有助于致癌。然而，介导 B[a] PDE 肿瘤促进作用的机制仍不清楚。我们的结果表明，在小鼠表皮 Cl41 细胞中，B[a] PDE 处理导致 AP-1 及其上游 MAPK（包括 ERK、JNK 和 p38K）显着激活。 B[a] PDE 暴露还导致磷脂酰肌醇 3-激酶 (PI-3K)、Akt 和 p70 S6 激酶 (p70(S6k)) 的激活。用 PI-3K 抑制剂、渥曼青霉素或 Ly294002 预处理细胞可抑制 B[a]PDE 诱导的 AP-1 反式激活。相反，用雷帕霉素抑制p70(S6k)没有表现出任何抑制作用。 PI-3K 显性失活突变体 Deltap85 的过度表达会损害 B[a]PDE 诱导的 PI-3K、Akt 和 AP-1 反式激活。此外，显性失活 Akt 突变体 Akt-T308A/S473A 的过表达可阻断 B[a]PDE 诱导的 Akt、AP-1 和 JNK 激活，但不影响 p70S6k、ERK 和 p38 激酶的激活。这些结果表明，B[a] PDE 能够诱导 AP-1 反式激活，并且这种 AP-1 诱导是通过 PI-3K/Akt/JNKs 依赖性和 p70(S6k) 独立途径特异性的。这项研究还表明，Akt-T308A/S473A 通过损害 JNK 通路特异性阻断 B[a]PDE 诱导的 AP-1 激活。这些发现将帮助我们了解 B[a] PDE 致癌作用所涉及的信号转导途径。
Mouse skin tumorigenicity studies indicate that benzo[a]-pyrene-7,8-diol-9,10-epoxide (B[a]PDE) contributes to carcinogenesis as both a tumor initiator and promoter. However, the mechanisms that mediate B[a] PDE tumor promotion effects remain unclear. Our results demonstrated that in mouse epidermal Cl41 cells, B[a] PDE treatment resulted in marked activation of AP-1 and its upstream MAPKs, including ERKs, JNKs and p38K. B[a] PDE exposure also led to activation of phosphotidy-linositol 3-kinase (PI-3K), Akt and p70 S6 kinase (p70(S6k)). B[a]PDE-induced AP-1 transactivation was inhibited by pretreatment of cells with PI-3K inhibitors, wortmannin or Ly294002. In contrast, inhibition of p70(S6k) with rapamycin did not show any inhibitory effects. An overexpression of dominant-negative mutant of PI-3K, Deltap85, impaired B[a]PDE-induced activation of PI-3K, Akt and AP-1 transactivation. Furthermore, an overexpression of dominant-negative Akt mutant, Akt-T308A/S473A, blocked B[a]PDE-induced activation of Akt, AP-1 and JNKs, while it did not affect the activation of p70S6k, ERKs and p38 kinase. These results demonstrated that B[a] PDE was able to induce AP-1 transactivation and this AP-1 induction was specific through PI-3K/Akt/JNKs-dependent and p70(S6k)-independent pathways. This study also indicated that Akt-T308A/S473A blocks B[a]PDE-induced AP-1 activation specific through impairing JNK pathway. These findings will help us to understand the signal transduction pathways involved in the carcinogenic effects of B[a] PDE.