Rhodes N, Innes C L, Propst F, Paules R S
Growth Control and Cancer Group, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Oncogene. 1997 Jun 26;14(25):3017-27. doi: 10.1038/sj.onc.1201158.
Serum deprived v-mos-transformed NIH3T3 cells are unable to enter a true quiescent state, but instead, arrest in the early G1 phase of the cell cycle. We have analysed several cell cycle regulatory proteins in these G1 arrested cells and show altered regulation in the expression and activity of certain cyclins and cyclin-dependent kinases. In particular, p34cdc2, cyclin A, cyclin D and cyclin E are not appropriately down-regulated in serum starved, G1 arrested, v-mos-transformed cells as compared with quiescent NIH3T3 cells. Furthermore, serum starved v-mos-transformed cells have elevated histone H1 kinase activity associated with cyclin A, cyclin E, p33cdk2, and p34cdc2. Using a metallothionein-inducible c-mos(mu) expression system, we show that c-mos(mu) induction in quiescent NIH3T3 cells causes elevated expression of p34cdc2. However, this induction of c-mos(mu) and subsequent expression of p34cdc2 was not sufficient to promote significant entry of cells into S phase. Analysis of extracts from serum starved v-H-ras, v-src, and tpr-met transformed NIH3T3 cells demonstrates that these oncogene-transformed cells also contain elevated levels of p34cdc2. We propose that the altered regulation of these critical cell cycle regulatory molecules, and specifically the inability to fully downregulate their activity, contributes significantly to neoplastic transformation and subsequent unregulated growth of tumor cells.
血清饥饿的v-mos转化NIH3T3细胞无法进入真正的静止状态，而是停滞在细胞周期的G1早期阶段。我们分析了这些G1期停滞细胞中的几种细胞周期调节蛋白，发现某些细胞周期蛋白和细胞周期蛋白依赖性激酶的表达和活性调节发生了改变。特别是，与静止的NIH3T3细胞相比，在血清饥饿、G1期停滞的v-mos转化细胞中，p34cdc2、细胞周期蛋白A、细胞周期蛋白D和细胞周期蛋白E没有得到适当的下调。此外，血清饥饿的v-mos转化细胞中与细胞周期蛋白A、细胞周期蛋白E、p33cdk2和p34cdc2相关的组蛋白H1激酶活性升高。使用金属硫蛋白诱导的c-mos（mu）表达系统，我们发现静止的NIH3T3细胞中c-mos（mu）的诱导会导致p34cdc2表达升高。然而，这种c-mos（mu）的诱导以及随后p34cdc2的表达不足以促进细胞大量进入S期。对血清饥饿的v-H-ras、v-src和tpr-met转化NIH3T3细胞提取物的分析表明，这些癌基因转化细胞中p34cdc2水平也升高。我们认为，这些关键细胞周期调节分子的调节改变，特别是无法完全下调其活性，对肿瘤细胞的肿瘤转化和随后的失控生长有显著贡献。
