p53 regulates Stat3 phosphorylation and DNA binding activity in human prostate cancer cells expressing constitutively active Stat3
p53 regulates Stat3 phosphorylation and DNA binding activity in human prostate cancer cells expressing constitutively active Stat3
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DOI：
10.1038/sj.onc.1205426
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发表时间：
2002-05-02
期刊：
影响因子：
8
通讯作者：
Hsieh, JT
中科院分区：
文献类型：
--
作者：
Lin, J;Tang, H;Hsieh, JT
信号转导子和转录激活子3（Stat 3）的组成性激活和p53的突变都在人前列腺癌细胞中常见地检测到。我们试图研究野生型（wt）p53是否对Stat 3有功能调节。我们的研究结果表明，野生型p53的表达，而不是突变型p53显着减少酪氨酸磷酸化的Stat 3和抑制Stat 3 DNA结合活性在DU 145和大津前列腺癌细胞系，表达组成型活性Stat 3。p53下游靶点p21（WAF-1）的表达对Stat 3磷酸化没有任何抑制作用。野生型p53而非p21（WAF-1）在这些前列腺癌细胞中诱导显著的凋亡。野生型p53的表达没有引起磷酸化非依赖性Stat 3蛋白的减少和三种无关蛋白激酶ERK 1、ERK 2（ERK 1/2）和AKT磷酸化的减少。有趣的是，在DU 145和大津前列腺癌细胞中，在存在高水平磷酸化AKT和ERK 1/2的情况下发生p53依赖性凋亡。此外，我们评估了一系列已建立的人前列腺癌、乳腺癌和卵巢癌细胞系，发现所有表达组成型活性Stat 3的癌细胞系仅含有突变或缺失的p53。这些结果的一个含义是p53的抗增殖活性可能与癌细胞中的组成性Stat 3信号不相容。
Constitutive activation of the signal transducer and activator of transcription 3 (Stat3) and mutation of the p53 are both commonly detected in human prostate cancer cells. We sought to investigate whether there is functional regulation of Stat3 by wild-type (wt) p53. Our results demonstrate that expression of wt p53 but not mutant p53 significantly reduced tyrosine phosphorylation of Stat3 and inhibited Stat3 DNA binding activity in both DU145 and Tsu prostate cancer cell lines that express constitutively active Stat3. Expression of the p53 downstream target, p21(WAF-1), did not have any inhibitory effect on Stat3 phosphorylation. Wt p53 but not p21(WAF-1) induced dramatic apoptosis in these prostate cancer cells. Expression of wt p53 did not cause a reduction of phosphorylation-independent Stat3 protein and reduction of phosphorylation of three unrelated protein kinases, ERK1, ERK2 (ERK1/2), and AKT. Interestingly, p53-dependent apoptosis occurred in the presence of high levels of phosphorylated AKT and ERK1/2 in both DU145 and Tsu prostate cancer cells. Further, we evaluated a series of established human prostate, breast, and ovarian cancer cell lines and found that all cancer cell lines expressing constitutively active Stat3, only harbor mutated or deleted p53. One implication of these results is that the anti-proliferative activities of p53 may not be compatible with the constitutive Stat3 signal in cancer cells.