Ultraviolet-B-induced G1 arrest is mediated by downregulation of cyclin-dependent kinase 4 in transformed keratinocytes lacking functional p53
Ultraviolet-B-induced G1 arrest is mediated by downregulation of cyclin-dependent kinase 4 in transformed keratinocytes lacking functional p53
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DOI：
10.1046/j.1523-1747.2002.01734.x
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发表时间：
2002-05-01
影响因子：
6.5
通讯作者：
Gautier, J
中科院分区：
文献类型：
--
作者：
Kim, AL;Athar, M;Gautier, J
为了确定紫外线 B 诱导的皮肤肿瘤发生的潜在新靶点，我们评估了紫外线 B 暴露对 p53 突变的转化角质形成细胞的细胞周期进程的影响。我们发现，人表皮样癌 A431 细胞的 UV-B 暴露会导致异步生长和同步细胞的 G1 细胞周期停滞。在暴露于低至 10 mJ/cm(2) 的 UV-B 剂量后，观察到 G1 细胞群显着增加。当用紫外线-B 照射时，在 G1 期与含羞草碱同步的细胞不会退出 G1 期。 G1 细胞周期停滞与视网膜母细胞瘤蛋白过度磷酸化形式的减少有关，这种减少在 4 小时内即可检测到，并在 12 小时内逐渐消失。我们还观察到细胞周期蛋白 D1、D2 和 D3 以及细胞周期蛋白依赖性激酶 4 蛋白的减少，以及细胞周期蛋白依赖性激酶 4/细胞周期蛋白 D1 相关激酶活性的伴随减少，而在此期间，紫外线 B 暴露对细胞周期蛋白依赖性激酶 2 和细胞周期蛋白依赖性激酶 6 水平没有影响。将细胞与蛋白酶体抑制剂 MG-115 和 MG-132 一起孵育可防止细胞周期蛋白 D1、D2 和 D3 以及细胞周期蛋白依赖性激酶 4 蛋白的减少。综上所述，我们的结果表明，A431 细胞中紫外线 B 诱导的细胞周期停滞是由细胞周期蛋白依赖性激酶 4 下调介导的。这确定了 UV-B 照射后转化角质形成细胞中 G1 细胞周期停滞的新途径。
In order to identify potential novel targets for ultraviolet-B-induced skin tumorigenesis, we assessed the effect of ultraviolet-B exposure on cell cycle progression of transformed keratinocytes with mutant p53. We show that ultraviolet-B exposure of human epidermoid carcinoma A431 cells results in G1 cell cycle arrest in both asynchronously growing and synchronized cells. A significant increase in G1 cell population was observed following exposure to doses of ultraviolet-B as low as 10 mJ per cm(2) . When irradiated with ultraviolet-B, cells synchronized in G1 with mimosine did not exit G1. G1 cell cycle arrest was associated with a decrease in the hyperphosphorylated forms of retinoblastoma protein that was detectable within 4 h and gradually disappeared by 12 h. We also observed a decrease in cyclins D1, D2, and D3, and cyclin-dependent kinase 4 proteins, and a concomitant decrease in cyclin-dependent kinase 4/cyclin D1 associated kinase activity, whereas ultraviolet-B exposure had no effect on cyclin-dependent kinase 2 and cyclin-dependent kinase 6 levels during this time period. Incubation of cells with proteasome inhibitors MG-115 and MG-132 prevented the decrease in cyclin D1, D2, and D3, and cyclin-dependent kinase 4 protein. Taken together, our results suggest that ultraviolet-B-induced cell cycle arrest in A431 cells is mediated by cyclin-dependent kinase 4 downregulation. This identifies a novel pathway for G1 cell cycle arrest in transformed keratinocytes following ultraviolet-B irradiation.