title: p21 Waf1/Cip1 expression by curcumin in U-87MG human glioma cells: role of early growth response-1 expression.
abstract: 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.
authors.affiliation: Department of Biomedical Science and Technology, Research Center for Transcription Control, Institute of Biomedical Science and Technology, Konkuk University, Seoul, Korea.
authors.forename: Byeong Hyeok
authors.initials: BH
authors.lastname: Choi
authors.forename: Chang Gun
authors.initials: CG
authors.lastname: Kim
authors.forename: Young-Seuk
authors.initials: YS
authors.lastname: Bae
authors.forename: Yoongho
authors.initials: Y
authors.lastname: Lim
authors.forename: Young Han
authors.initials: YH
authors.lastname: Lee
authors.forename: Soon Young
authors.initials: SY
authors.lastname: Shin
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D003474:Curcumin / Q000494:pharmacology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis*; D051766:Early Growth Response Protein 1 / Q000096:biosynthesis* / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000378:metabolism*; D006801:Humans; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000378:metabolism; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D050807:ets-Domain Protein Elk-1 / Q000378:metabolism
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C497325:EGR1 protein, human; C494112:ELK1 protein, human; D051766:Early Growth Response Protein 1; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D050807:ets-Domain Protein Elk-1; D048055:Mitogen-Activated Protein Kinase 8; D003474:Curcumin