title: The ETS family transcription factor ELK-1 regulates induction of the cell cycle-regulatory gene p21(Waf1/Cip1) and the BAX gene in sodium arsenite-exposed human keratinocyte HaCaT cells.
abstract: Cyclin-dependent kinase inhibitor (CDKN1A), often referred to as p21(Waf1/Cip1) (p21), is induced by a variety of environmental stresses. Transcription factor ELK-1 is a member of the ETS oncogene superfamily. Here, we show that ELK-1 directly trans-activates the p21 gene, independently of p53 and EGR-1, in sodium arsenite (NaASO(2))-exposed HaCaT cells. Promoter deletion analysis and site-directed mutagenesis identified the presence of an ELK-1-binding core motif between -190 and -170 bp of the p21 promoter that confers inducibility by NaASO(2). Chromatin immunoprecipitation and electrophoretic mobility shift analyses confirmed the specific binding of ELK-1 to its putative binding sequence within the p21 promoter. In addition, NaASO(2)-induced p21 promoter activity was enhanced by exogenous expression of ELK-1 and reduced by expression of siRNA targeted to ELK-1 mRNA. The importance of ELK-1 in response to NaASO(2) was further confirmed by the observation that stable expression of ELK-1 siRNA in HaCaT cells resulted in the attenuation of NaASO(2)-induced p21 expression. Although ELK-1 was activated by ERK, JNK, and p38 MAPK in response to NaASO(2), ELK-1-mediated activation of the p21 promoter was largely dependent on ERK. In addition, EGR-1 induced by ELK-1 seemed to be involved in NaASO(2)-induced expression of BAX. This supports the view that the ERK/ELK-1 cascade is involved in p53-independent induction of p21 and BAX gene expression.
authors.affiliation: SMART Institute of Advanced Biomedical Science, Konkuk University, Seoul 143-701, Korea. shinsy@konkuk.ac.kr
authors.forename: Soon Young
authors.initials: SY
authors.lastname: Shin
authors.forename: Chang Gun
authors.initials: CG
authors.lastname: Kim
authors.forename: Yoongho
authors.initials: Y
authors.lastname: Lim
authors.forename: Young Han
authors.initials: YH
authors.lastname: Lee
mesh_terms: D018053:Arsenites / Q000494:pharmacology*; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis* / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D015603:Keratinocytes; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020218:Response Elements; D017670:Sodium Compounds / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis* / Q000235:genetics; D050807:ets-Domain Protein Elk-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D018053:Arsenites; C494826:BAX protein, human; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C494112:ELK1 protein, human; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D017670:Sodium Compounds; D051028:bcl-2-Associated X Protein; D050807:ets-Domain Protein Elk-1; C017947:sodium arsenite; D020929:Mitogen-Activated Protein Kinase Kinases