Lin Jiayuh, Jin Xiaohong, Rothman Kori, Lin Huey-Jen, Tang Huaijing, Burke William
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan 48109-0936, USA.
Cancer Res. 2002 Jan 15;62(2):376-80.
The constitutive activation of the Stat3 oncogene product and mutation of the p53 tumor suppressor are both frequently detected in human breast cancer. We sought to determine whether there is functional regulation of Stat3 by wild-type (wt) p53. We demonstrate that expression of wt p53, but not mutant p53, significantly diminished phosphorylation of Stat3, reduced Stat3 DNA binding activity, and inhibited Stat3-dependent transcriptional activity in breast cancer cells expressing constitutively active Stat3. Expression of wt p53 did not cause a reduction in the phosphorylation of three unrelated protein kinases in other signal transduction pathways, AKT, extracellular signal-regulated kinase (ERK)1, and ERK2 or a reduction of phosphorylation of epidermal growth factor receptor. Furthermore, the expression of the p53 downstream target, p21(WAF-1), did not have an inhibitory effect on Stat3 phosphorylation. Wt p53 also induced significant apoptosis in breast cancer cell lines that express constitutively active Stat3. Interestingly, the p53-dependent apoptosis occurred in the presence of high levels of phosphorylated AKT and ERK1/2. Therefore, these findings demonstrate a novel p53-dependent cellular process that regulates Stat3 phosphorylation and activity.
信号转导和转录激活因子3（Stat3）癌基因产物的组成性激活以及p53肿瘤抑制因子的突变在人类乳腺癌中均经常被检测到。我们试图确定野生型（wt）p53是否对Stat3有功能调控作用。我们证明，在组成性激活Stat3的乳腺癌细胞中，wt p53的表达而非突变型p53的表达，能显著减少Stat3的磷酸化，降低Stat3的DNA结合活性，并抑制Stat3依赖的转录活性。wt p53的表达并未导致其他信号转导途径中三种不相关蛋白激酶（AKT、细胞外信号调节激酶（ERK）1和ERK2）的磷酸化减少，也未导致表皮生长因子受体的磷酸化减少。此外，p53下游靶点p21（WAF-1）的表达对Stat3磷酸化没有抑制作用。wt p53还能在组成性激活Stat3的乳腺癌细胞系中诱导显著的细胞凋亡。有趣的是，p53依赖的细胞凋亡在高水平磷酸化的AKT和ERK1/2存在的情况下发生。因此，这些发现证明了一种新的p53依赖的细胞过程，该过程调控Stat3的磷酸化和活性。
