Sekine Y, Tsuji S, Ikeda O, Sato N, Aoki N, Aoyama K, Sugiyama K, Matsuda T
Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Oncogene. 2006 Sep 21;25(42):5801-6. doi: 10.1038/sj.onc.1209578. Epub 2006 Apr 24.
Signal transducer and activator of transcription 3 (STAT3), which mediates biological actions in many physiological processes, is activated by cytokines and growth factors, and has been reported to be constitutively activated in numerous cancer cells. In this study, we examined whether low molecular weight-dual specificity phosphatase two (LMW-DSP2) is involved in the regulation of the interleukin 6 (IL-6)/leukemia inhibitory factor (LIF)/STAT3-mediated signaling pathway. IL-6/LIF-induced LMW-DSP2 expression in murine testicular or hepatoma cell lines, while LMW-DSP2 overexpression in 293T cells suppressed IL-6-induced phosphorylation and activation of STAT3. Furthermore, LMW-DSP2 suppressed the expression of IL-6-induced endogenous genes. In contrast, small-interfering RNA-mediated reduction of LMW-DSP2 expression enhanced IL-6-induced STAT3-dependent transcription. In fact, LMW-DSP2 interacted with STAT3 in vivo and endogenous LMW-DSP2 bound to STAT3 in murine testicular GC-1 cells. These results strongly suggest that LMW-DSP2 acts as a negative regulator of the IL-6/LIF/STAT3-mediated signaling pathway.
信号转导与转录激活因子3（STAT3）在许多生理过程中介导生物学作用，它可被细胞因子和生长因子激活，并且据报道在众多癌细胞中持续激活。在本研究中，我们检测了低分子量双特异性磷酸酶2（LMW-DSP2）是否参与白细胞介素6（IL-6）/白血病抑制因子（LIF）/STAT3介导的信号通路的调控。IL-6/LIF诱导小鼠睾丸或肝癌细胞系中LMW-DSP2的表达，而在293T细胞中过表达LMW-DSP2可抑制IL-6诱导的STAT3磷酸化和激活。此外，LMW-DSP2抑制IL-6诱导的内源性基因的表达。相反，小干扰RNA介导的LMW-DSP2表达降低增强了IL-6诱导的STAT3依赖性转录。事实上，LMW-DSP2在体内与STAT3相互作用，并且内源性LMW-DSP2在小鼠睾丸GC-1细胞中与STAT3结合。这些结果强烈表明LMW-DSP2作为IL-6/LIF/STAT3介导的信号通路的负调节因子发挥作用。
