Cipriano S C, Chen Y Q
Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Oncogene. 1998 Sep 24;17(12):1549-56. doi: 10.1038/sj.onc.1202069.
TGF-beta is a potent growth inhibitor of epithelial cells. However, many transformed cells have lost their sensitivity to this growth inhibitory effect. The molecular mechanism of such insensitivity is not yet understood. Here, we have studied the TGF-beta1 effect on normal human prostate and carcinoma cells. Our results showed that normal cells were sensitive to growth inhibition, whereas tumor cells were not or only minimally inhibited regardless of the concentration of TGF-beta1 (20 to 80 pM) or time of exposure (1-5 days). p21WAF1/Cip1/Sdi1 and p15INK4B but not p27KIP1 were detectable by Western blotting in normal and tumor cells. TGF-beta1 treatment increased the association of p21WAF1/Cip1/Sdi1 with the Cdk2/cyclin E complex in both normal and prostate tumor cells. However, there was no increase in the association of p15INK4B nor p27Kip1 with the Cdk/cyclin complexes. In normal cells, the increase in the association of p21WAF1/Cip1/Sdi1. With the Cdk2/cyclin E complex resulted in inhibition of the Cdk2 activity. In contrast, although there was an increase in the association of p21WAF1/Cip1/Sdi1 with the Cdk2/cyclin E complex in tumor cells, there was no inhibition of the Cdk2 activity. These results indicate that a lack of inhibition of the Cdk2 activity correlates with insensitivity to TGF-beta1 in prostate tumor cells.
转化生长因子-β（TGF-β）是上皮细胞的一种强效生长抑制剂。然而，许多转化细胞已失去对这种生长抑制作用的敏感性。这种不敏感性的分子机制尚不清楚。在此，我们研究了TGF-β1对正常人类前列腺细胞和癌细胞的作用。我们的结果表明，正常细胞对生长抑制敏感，而肿瘤细胞则不然，无论TGF-β1的浓度（20至80皮摩尔）或暴露时间（1至5天）如何，肿瘤细胞要么不被抑制，要么仅受到轻微抑制。通过蛋白质印迹法在正常细胞和肿瘤细胞中均可检测到p21WAF1/Cip1/Sdi1和p15INK4B，但检测不到p27KIP1。TGF-β1处理增加了正常细胞和前列腺肿瘤细胞中p21WAF1/Cip1/Sdi1与细胞周期蛋白依赖性激酶2（Cdk2）/细胞周期蛋白E复合物的结合。然而，p15INK4B和p27Kip1与细胞周期蛋白依赖性激酶/细胞周期蛋白复合物的结合并未增加。在正常细胞中，p21WAF1/Cip1/Sdi1与Cdk2/细胞周期蛋白E复合物结合的增加导致Cdk2活性受到抑制。相比之下，尽管肿瘤细胞中p21WAF1/Cip1/Sdi1与Cdk2/细胞周期蛋白E复合物的结合有所增加，但Cdk2活性并未受到抑制。这些结果表明，Cdk2活性缺乏抑制与前列腺肿瘤细胞对TGF-β1不敏感相关。
