Wu Frederick Y, Wang Shizhen Emily, Sanders Melinda E, Shin Incheol, Rojo Federico, Baselga Jose, Arteaga Carlos L
Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Cancer Res. 2006 Feb 15;66(4):2162-72. doi: 10.1158/0008-5472.CAN-05-3304.
We generated a p27(Kip1) mutant (p27deltaNLS) that localized exclusively in cell cytosol. Expression of p27deltaNLS in MCF7 breast cancer cells down-regulated RhoA and increased motility, survival, and Akt levels without an effect on cell cycle distribution. RNA interference of p27 in U87 glioma cells, which express p27 predominantly in the cytoplasm, inhibited motility and survival. Conversely, knockdown of p27 in COS7 cells, with >95% nuclear p27 expression, accelerated proliferation but had no effect on motility or survival. U87 cells in which p27 had been eliminated by RNA interference exhibited lower Akt levels, shorter Akt turnover, and markedly impaired tumorigenicity in vivo. These xenografts were less invasive and exhibited increased apoptosis compared with p27-expressing tumors. Expression of cytosolic p27 in primary human breast carcinomas correlated linearly with Akt content as measured by immunohistochemistry. These data suggest that cytoplasmic p27 can exert oncogenic functions by modulating Akt stability, cell survival, and tumorigenicity.
我们构建了一种仅定位于细胞质的p27（Kip1）突变体（p27deltaNLS）。在MCF7乳腺癌细胞中表达p27deltaNLS可下调RhoA，增加细胞运动性、存活率以及Akt水平，且对细胞周期分布无影响。在U87胶质瘤细胞中，p27主要在细胞质中表达，对其进行RNA干扰可抑制细胞运动性和存活率。相反，在p27核表达>95%的COS7细胞中敲低p27可加速细胞增殖，但对细胞运动性或存活率无影响。通过RNA干扰消除p27的U87细胞表现出较低的Akt水平、较短的Akt周转时间，并且在体内的致瘤性明显受损。与表达p27的肿瘤相比，这些异种移植瘤的侵袭性较低且凋亡增加。通过免疫组织化学检测，原发性人类乳腺癌中细胞质p27的表达与Akt含量呈线性相关。这些数据表明，细胞质p27可通过调节Akt稳定性、细胞存活和致瘤性发挥致癌功能。
