You Huihong, Yu Weiping, Munoz-Medellin Debbie, Brown Powel H, Sanders Bob G, Kline Kimberly
Department of Molecular Genetics and Microbiology/C0900 School of Biological Sciences, The University of Texas at Austin, 78712-1097, USA.
Mol Carcinog. 2002 Apr;33(4):228-36. doi: 10.1002/mc.10040.
RRR-alpha-tocopheryl succinate (vitamin E succinate, VES) induces differentiation of human breast cancer cells. Previous studies ruled out transforming growth factor-beta and c-jun N-terminal kinase involvement in VES-induced differentiation but implicated extracellular signal-regulated kinases (ERKs). Here we show that dominant-negative mutants of either mitogen-activated protein kinase kinase (MEK) 1 or ERK1 blocked VES-induced differentiation of MDA-MB-435 cells, as measured by induction of cytokeratin 18 and p21 (Waf1/Cip1) proteins. Blockage of c-jun protein expression using c-jun antisense oligonucleotides or expression of an inducible dominant-negative c-jun mutant protein inhibited VES-induced differentiation. Elevated expression of wild-type c-jun alone was sufficient to induce cellular differentiation. A role for p21 (Waf1/Cip1) is implicated, in that p21 antisense oligomers blocked VES-induced differentiation. In summary, MEK1, ERK1, the transcription factor c-jun, and the cyclin-dependent kinase inhibitor p21 (Waf1/Cip1) play a part in VES-induced differentiation of human MDA-MB-435 breast cancer cells.
RRR-α-生育酚琥珀酸酯（维生素E琥珀酸酯，VES）可诱导人乳腺癌细胞分化。先前的研究排除了转化生长因子-β和c-jun氨基末端激酶参与VES诱导的分化过程，但表明细胞外信号调节激酶（ERK）与之有关。在此我们发现，丝裂原活化蛋白激酶激酶（MEK）1或ERK1的显性负性突变体可阻断VES诱导的MDA-MB-435细胞分化，这可通过细胞角蛋白18和p21（Waf1/Cip1）蛋白的诱导来衡量。使用c-jun反义寡核苷酸阻断c-jun蛋白表达或诱导性显性负性c-jun突变蛋白的表达可抑制VES诱导的分化。单独野生型c-jun表达的升高足以诱导细胞分化。p21（Waf1/Cip1）的作用也有涉及，因为p21反义寡聚物可阻断VES诱导的分化。总之，MEK1、ERK1、转录因子c-jun和细胞周期蛋白依赖性激酶抑制剂p21（Waf1/Cip1）在VES诱导的人MDA-MB-435乳腺癌细胞分化中发挥作用。
