Ma Z Q, Chua S S, DeMayo F J, Tsai S Y
Department of Cell Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, TX 77030, USA.
Oncogene. 1999 Aug 12;18(32):4564-76. doi: 10.1038/sj.onc.1202809.
Cdc25 A and B are dual-specificity phosphatases which have been implicated in neoplastic transformation. Although Cdc25A and Cdc25B have been found to be over-expressed in many cancer cell lines and primary tumors, the physiological roles of Cdc25A and B in vivo are largely undefined. To investigate the roles of these proteins in the oncogenic transformation of the mammary gland we used the mouse mammary tumor virus (MMTV) promoter to target over-expression of the Cdc25B transgene in the mammary glands of transgenic mouse lines. Here we report that the over-expression of Cdc25B enhances the proliferation of mammary epithelial cells resulting in the formation of precocious alveolar hyperplasia. At the molecular level, marked increases in cyclin D1 protein have been found in transgenic mammary epithelial cells. The accelerated growth rate of the mammary epithelial cells could also be attributed to the increased levels of cyclin E/cdk2 activity. In addition, a pronounced decrease in apoptosis was also observed during the involution of mammary gland. The reduction of apoptosis during involution correlated well with the reduced expression of c-myc and p53, both of which have been implicated in apoptosis. Taken together, our results clearly indicate that the deregulated expression of Cdc25B generates mammary gland hyperplasia.
Cdc25 A和B是双特异性磷酸酶，与肿瘤转化有关。尽管已发现Cdc25A和Cdc25B在许多癌细胞系和原发性肿瘤中过度表达，但它们在体内的生理作用在很大程度上仍不明确。为了研究这些蛋白在乳腺致癌转化中的作用，我们使用小鼠乳腺肿瘤病毒（MMTV）启动子在转基因小鼠品系的乳腺中靶向过表达Cdc25B转基因。在此我们报告，Cdc25B的过表达增强了乳腺上皮细胞的增殖，导致早熟性肺泡增生的形成。在分子水平上，在转基因乳腺上皮细胞中发现细胞周期蛋白D1蛋白显著增加。乳腺上皮细胞加速的生长速率也可归因于细胞周期蛋白E/cdk2活性水平的增加。此外，在乳腺退化过程中还观察到细胞凋亡明显减少。退化过程中细胞凋亡的减少与c-myc和p53表达的降低密切相关，这两者都与细胞凋亡有关。综上所述，我们的结果清楚地表明，Cdc25B的失调表达会导致乳腺增生。
