Choi Byeong Hyeok, Kim Chang Gun, Bae Young-Seuk, Lim Yoongho, Lee Young Han, Shin Soon Young
Department of Biomedical Science and Technology, Research Center for Transcription Control, Institute of Biomedical Science and Technology, Konkuk University, Seoul, Korea.
Cancer Res. 2008 Mar 1;68(5):1369-77. doi: 10.1158/0008-5472.CAN-07-5222.
Curcumin, a natural compound, is a well-known chemopreventive agent with potent anticarcinogenic activity in a wide variety of tumor cells. Curcumin inhibits cancer cell proliferation in part by suppressing cyclin D1 and inducing expression of the cyclin-dependent kinase inhibitor p21(Waf1/Cip1). Both p53-dependent and p53-independent mechanisms regulate p21(Waf1/Cip1) expression, but the mechanism by which curcumin regulates p21(Waf1/Cip1) expression remains unknown. Here, we report that transcription of the p21(Waf1/Cip1) gene is activated by early growth response-1 (Egr-1) independently of p53 in response to curcumin treatment in U-87MG human glioblastoma cells. Egr-1 is a transcription factor that helps regulate differentiation, growth, and apoptosis in many cell types. Egr-1 expression is induced by curcumin through extracellular signal-regulated kinase (ERK) and c-Jun NH(2)-terminal kinase (JNK), but not the p38, mitogen-activated protein kinase (MAPK) pathways, which mediate the transactivation of Elk-1. Transient expression of Egr-1 enhanced curcumin-induced p21(Waf1/Cip1) promoter activity, whereas suppression of Egr-1 expression by small interfering RNA abrogated the ability of curcumin to induce p21(Waf1/Cip1) promoter activity. In addition, stable knockdown of Egr-1 expression in U-87MG cells suppressed curcumin-induced p21 expression. Our results indicate that ERK and JNK MAPK/Elk-1/Egr-1 signal cascade is required for p53-independent transcriptional activation of p21(Waf1/Cip1) in response to curcumin in U-87MG human glioblastoma cells.
姜黄素是一种天然化合物，是一种著名的化学预防剂，在多种肿瘤细胞中具有强大的抗癌活性。姜黄素部分通过抑制细胞周期蛋白D1和诱导细胞周期蛋白依赖性激酶抑制剂p21（Waf1/Cip1）的表达来抑制癌细胞增殖。p53依赖性和p53非依赖性机制均调节p21（Waf1/Cip1）的表达，但姜黄素调节p21（Waf1/Cip1）表达的机制尚不清楚。在此，我们报告在U-87MG人胶质母细胞瘤细胞中，响应姜黄素处理，p21（Waf1/Cip1）基因的转录由早期生长反应-1（Egr-1）独立于p53激活。Egr-1是一种转录因子，有助于调节多种细胞类型中的分化、生长和凋亡。姜黄素通过细胞外信号调节激酶（ERK）和c-Jun NH(2)-末端激酶（JNK）诱导Egr-1表达，但不通过介导Elk-1反式激活的p38丝裂原活化蛋白激酶（MAPK）途径。Egr-1的瞬时表达增强了姜黄素诱导的p21（Waf1/Cip1）启动子活性，而小干扰RNA抑制Egr-1表达则消除了姜黄素诱导p21（Waf1/Cip1）启动子活性的能力。此外，U-87MG细胞中Egr-1表达的稳定敲低抑制了姜黄素诱导的p21表达。我们的结果表明，ERK和JNK MAPK/Elk-1/Egr-1信号级联对于U-87MG人胶质母细胞瘤细胞中响应姜黄素的p21（Waf1/Cip1）的p53非依赖性转录激活是必需的。
