Constitutive activation of Stat3 in fibroblasts transformed by diverse oncoproteins and in breast carcinoma cells.
Constitutive activation of Stat3 in fibroblasts transformed by diverse oncoproteins and in breast carcinoma cells.
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发表时间：
1997-12
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通讯作者：
R. Garcia;Chao-Lan Yu;Anne K. Hudnall;Robyn Catlett;Knstie L Nelson;T. Smithgall;D. Fujita;S. Et
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作者：
R. Garcia;Chao-Lan Yu;Anne K. Hudnall;Robyn Catlett;Knstie L Nelson;T. Smithgall;D. Fujita;S. Et
信号转导子和转录激活子 (STAT) 最初被认为是参与介导 IFN 反应的信号通路的关键组成部分。先前的研究表明，Src 癌蛋白持续激活 STAT 家族成员 Stat3。在这项研究中，我们研究了一组被不同病毒癌蛋白稳定转化的啮齿动物成纤维细胞系中的 STAT 激活。使用 v-Src 的温度敏感突变体，我们确定 Stat3 在细胞转化从不允许温度转变为允许温度的 15 分钟内被激活。这一发现表明 Stat3 激活需要 v-Src 酪氨酸激酶活性，并表明 Stat3 接近于 Src 启动的信号传导。此外，Stat3 激活是由另一种非受体酪氨酸激酶 v-Fps 诱导的；通过多瘤病毒中 T 抗原，激活 Src 家族激酶；以及 v-Sis，它充当血小板衍生生长因子受体的配体。相比之下，通过不同机制转化细胞的 SV40 大 T 抗原以及位于酪氨酸激酶下游信号通路中的 v-Ras 和 v-Raf 癌蛋白不会激活 Stat3。我们没有在所研究的病毒癌蛋白转化的成纤维细胞中检测到 Stat1、Stat5 或 Stat6 的显着激活。此外，在永生化的正常人乳腺上皮细胞中，Stat3 会因表皮生长因子 (EGF) 而被激活，但不会因调蛋白而被激活。由于 c-Src 和 EGF 受体激酶的组成型激活与乳腺癌的进展相关，因此我们检查了源自乳腺癌的人类细胞系中 STAT 的激活。我们在九个乳腺癌细胞系中的五个中检测到 Stat3 的组成型激活，但在正常乳腺上皮细胞中未检测到。此外，使用 EGF 受体特异性抑制剂进行的实验表明，这些乳腺癌细胞系中 Stat3 的组成型激活不一定依赖于通过 EGF 受体的信号传导，尽管 EGF 刺激进一步增加了 Stat3 的激活。综上所述，我们的结果表明，Stat3 的选择性激活是致癌转化过程中的常见事件，直接或间接涉及特定酪氨酸激酶信号通路的激活。
Signal transducers and activators of transcription (STATs) were originally identified as key components of signaling pathways involved in mediating responses to IFNs. Previous studies showed that the Src oncoprotein constitutively activates one STAT family member, Stat3. In this study, we investigated STAT activation in a panel of rodent fibroblast cell lines stably transformed by diverse viral oncoproteins. Using a temperature-sensitive mutant of v-Src, we determined that Stat3 is activated within 15 min of shift from nonpermissive to permissive temperature for cell transformation. This finding indicates that v-Src tyrosine kinase activity is required for Stat3 activation and suggests that Stat3 is proximal to signaling initiated by Src. In addition, Stat3 activation is induced by another nonreceptor tyrosine kinase, v-Fps; by polyoma virus middle T antigen, which activates Src family kinases; and by v-Sis, which acts as a ligand for the platelet-derived growth factor receptor. In contrast SV40 large T antigen, which transforms cells through different mechanisms, and the v-Ras and v-Raf oncoproteins, which lie in signaling pathways downstream of tyrosine kinases, do not activate Stat3. We did not detect significant activation of Stat1, Stat5, or Stat6 in fibroblasts transformed by the viral oncoproteins investigated. Moreover, Stat3 is activated in response to epidermal growth factor (EGF) but not heregulins in immortalized normal human breast epithelial cells. Because constitutive activation of c-Src and EGF receptor kinases is associated with the progression of breast cancer, we examined activation of STATs in human cell lines derived from breast carcinomas. We detected constitutive activation of Stat3 in five of nine breast carcinoma cell lines but not in normal breast epithelial cells. Furthermore, experiments with an EGF receptor-specific inhibitor indicated that the constitutive activation of Stat3 in these breast carcinoma cell lines is not necessarily dependent on signaling through the EGF receptor, although EGF stimulation further increases Stat3 activation. Taken together, our results demonstrate that selective activation of Stat3 is a common event during oncogenic transformation that directly or indirectly involves activation of specific tyrosine kinase signaling pathways.