Loss of tumor suppressor p53 decreases PTEN expression and enhances signaling pathways leading to activation of activator protein 1 and nuclear factor kappaB induced by UV radiation.
Loss of tumor suppressor p53 decreases PTEN expression and enhances signaling pathways leading to activation of activator protein 1 and nuclear factor kappaB induced by UV radiation.
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DOI：
10.1158/0008-5472.can-04-4184
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发表时间：
2005-08
期刊：
影响因子：
11.2
通讯作者：
Jian Wang;W. Ouyang;Jingxia Li;Lixin Wei;Q. Ma;Zhuo Zhang;Q. Tong;Jié He;Chuanshu Huang
中科院分区：
文献类型：
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作者：
Jian Wang;W. Ouyang;Jingxia Li;Lixin Wei;Q. Ma;Zhuo Zhang;Q. Tong;Jié He;Chuanshu Huang
转录因子P53和磷酸酶PTEN是两种在抑制肿瘤发生中起重要作用的肿瘤抑制因子。然而，P53介导抗癌活性的机制以及P53和PTEN之间的关系还不是很清楚。在本研究中，我们发现，用P53依赖的转录激活抑制剂Pifithin-Alpha预处理小鼠表皮Cl41细胞，可显著增加紫外线诱导的激活蛋白1(AP-1)和核因子kappaB(NF-kappaB)的激活。与AP-1和核因子-kappaB的激活相一致，匹氟菊酯-α也能增强紫外线诱导的c-jun-NH2-激酶(JNK)和p38激酶的磷酸化，而对细胞外信号调节的激酶的磷酸化没有任何影响。此外，紫外线诱导的信号激活，包括JNK、p38激酶、Akt和p70S6K的磷酸化，在p53缺陷细胞(P53-/-)中显著增强，这可以被P53重组逆转。此外，通过其小干扰RNA下调P53的表达，也可引起紫外线辐射诱导的AP-1活性和Akt磷酸化水平的升高。这些结果表明，在细胞对紫外线辐射的反应中，P53对导致AP-1和NF-kappaB活化的细胞信号通路具有抑制作用。更重要的是，P53表达缺失导致PTEN蛋白表达下降，提示P53在PTEN表达调控中起关键作用。此外，野生型PTEN的过表达可抑制紫外线诱导的AP-1活性。由于PTEN是一种广为人知的磷酸酶，参与磷脂酰肌醇3-激酶(PI-3K)/Akt信号通路的调节，再加上PI-3K/Akt在肿瘤发生发展过程中对AP-1和NF-kappaB的激活起重要作用，我们推测抑癌基因P53对AP-1和NF-kappaB的抑制可能是通过PTEN介导的，这可能是P53蛋白抗癌活性的一个新机制。
Transcription factor p53 and phosphatase PTEN are two tumor suppressors that play essential roles in suppression of carcinogenesis. However, the mechanisms by which p53 mediates anticancer activity and the relationship between p53 and PTEN are not well understood. In the present study, we found that pretreatment of mouse epidermal Cl41 cells with pifithrin-alpha, an inhibitor for p53-dependent transcriptional activation, resulted in a marked increase in UV-induced activation of activator protein 1 (AP-1) and nuclear factor kappaB (NF-kappaB). Consistent with activation of AP-1 and NF-kappaB, pifithrin-alpha was also able to enhance the UV-induced phosphorylation of c-Jun-NH2-kinases (JNK) and p38 kinase, whereas it did not show any effect on phosphorylation of extracellular signal-regulated kinases. Furthermore, the UV-induced signal activation, including phosphorylation of JNK, p38 kinase, Akt, and p70S6K, was significantly enhanced in p53-deficient cells (p53-/-), which can be reversed by p53 reconstitution. In addition, knockdown of p53 expression by its small interfering RNA also caused the elevation of AP-1 activation and Akt phosphorylation induced by UV radiation. These results show that p53 has a suppressive activity on the cell signaling pathways leading to activation of AP-1 and NF-kappaB in cell response to UV radiation. More importantly, deficiency of p53 expression resulted in a decrease in PTEN protein expression, suggesting that p53 plays a critical role in the regulation of PTEN expression. In addition, overexpression of wild-type PTEN resulted in inhibition of UV-induced AP-1 activity. Because PTEN is a well-known phosphatase involved in the regulation of phosphatidylinositol 3-kinase (PI-3K)/Akt signaling pathway, taken together with the evidence that PI-3K/Akt plays an important role in the activation of AP-1 and NF-kappaB during tumor development, we anticipate that inhibition of AP-1 and NF-kappaB by tumor suppressor p53 seems to be mediated via PTEN, which may be a novel mechanism involved in anticancer activity of p53 protein.