Mulloy Roseann, Salinas Sara, Philips Alexandre, Hipskind Robert A
Institut de Génétique Moléculaire de Montpellier, CNRS, UMR 5535, IFR 122, 1919 Route de Mende, 34293 Montpellier 5, France.
Oncogene. 2003 Aug 21;22(35):5387-98. doi: 10.1038/sj.onc.1206839.
Transcriptional activation of the cyclin D1 gene is a key step in cell proliferation. Accordingly, cyclin D1 overexpression is frequently an early step in neoplastic transformation, particularly in mammary epithelium. Numerous studies have linked elevated cyclin D1 promoter activity to a sustained activation of the ERK1/2 cascade. Here we show that the ERK5 cascade, a distinct mitogen-induced MAPK pathway, can also drive cyclin D1 expression. In CCL39 cells, serum induces a strong, prolonged peak of ERK1/2 and ERK5 phosphorylation, and subsequently elevates cyclin D1 mRNA and protein levels. Overexpression of constitutively active MEK5 and wt ERK5 induces a cyclin D1 reporter gene (D1 -973-luciferase) at least as well as constitutively active MEK1. Activation is blocked by kinase-dead mutants of ERK5 and ERK2, respectively. Mutation of the CRE at -50 in the cyclin D1 promoter decreases activation by the ERK5 but not the ERK1/2 cascade. Importantly, expression of kinase-dead ERK5 diminishes endogenous cyclin D1 protein induction by serum in CCL39 cells and the breast cancer cell lines MCF-7 and HS579. These data identify the cyclin D1 gene as a novel target of the ERK5 cascade, an observation with important implications in cancers involving cyclin D1 deregulation.
细胞周期蛋白D1基因的转录激活是细胞增殖的关键步骤。因此，细胞周期蛋白D1的过表达通常是肿瘤转化的早期步骤，尤其是在乳腺上皮中。大量研究将细胞周期蛋白D1启动子活性的升高与ERK1/2级联的持续激活联系起来。在这里，我们表明ERK5级联，一种独特的丝裂原诱导的MAPK途径，也可以驱动细胞周期蛋白D1的表达。在CCL39细胞中，血清诱导ERK1/2和ERK5磷酸化出现强烈、持久的峰值，随后提高细胞周期蛋白D1的mRNA和蛋白质水平。组成型活性MEK5和野生型ERK5的过表达诱导细胞周期蛋白D1报告基因（D1 -973-荧光素酶）的效果至少与组成型活性MEK1一样好。激活分别被ERK5和ERK2的激酶失活突变体阻断。细胞周期蛋白D1启动子中-50处的CRE突变降低了ERK5级联的激活，但不影响ERK1/2级联的激活。重要的是，激酶失活的ERK5的表达减少了血清在CCL39细胞以及乳腺癌细胞系MCF-7和HS579中诱导的内源性细胞周期蛋白D1蛋白。这些数据确定细胞周期蛋白D1基因为ERK5级联的一个新靶点，这一发现对涉及细胞周期蛋白D1失调的癌症具有重要意义。
