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Prepublished online as a Blood First Edition Paper on January 23, 2003; DOI 10.1182/blood-2002-10-3174. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-10-3174v1 101/11/4551    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Hao, H. Articles by Ratnam, M. Search for Related Content PubMed PubMed Citation Articles by Hao, H. Articles by Ratnam, M. Related Collections Neoplasia Gene Expression Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 June 2003, Vol. 101, No. 11, pp. 4551-4560 NEOPLASIA Modulation of the folate receptor type gene by coordinate actions of retinoic acid receptors at activator Sp1/ets and repressor AP-1 sites Hong Hao, Huiling Qi, and Manohar Ratnam From the Department of Biochemistry and Molecular Biology, Medical College of Ohio, Toledo, OH. Folate receptor (FR) type is a promising target for therapeutic intervention in acute myelogenous leukemia (AML) owing particularly to its specific up-regulation in AML cells by all-trans retinoic acid (ATRA). Here we identify functional elements in the FR- gene and examine the molecular mechanism of transcriptional induction of FR- by ATRA. The basal promoter activity of FR- resulted from synergistic interaction between Sp1 and ets binding sites (EBSs) and repression by upstream AP-1–like elements, whose action required EBSs. A minimal promoter containing the Sp1 and ets elements was ATRA-responsive. The repressor elements bound Fos family proteins; association of the proteins with the repressor elements correlated negatively with FR- expression in peripheral blood neutrophils and monocytes and also in KG-1 (AML) cells grown in the absence or in the presence of ATRA. Furthermore, down-regulation of FR- in KG-1 cells treated with O-tetradecanoylphorbol 13-acetate (TPA) was accompanied by increased AP-1 binding to the repressor elements. From chromatin immunoprecipitation (ChIP) assays, the nuclear retinoic acid receptor (RAR) associated with the Sp1 region, and RARs and associated with the AP-1 and Sp1 regions; treatment of KG-1 cells with ATRA did not alter Sp1 binding but increased the association of RAR and decreased the association of RARs and . ATRA also decreased RAR expression levels. The results suggest that the FR- gene is a target for multiple coordinate actions of nuclear receptors for ATRA directly and indirectly acting on a transcriptional complex containing activating Sp1/ets and inhibitory AP-1 proteins. The multiple mechanisms favor the prediction that ATRA will induce FR- expression in a broad spectrum of AML cells. Further, optimal FR- induction may be expected when all 3 RAR subtypes bind agonist. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. B. Wu, K. Chen, X.-M. Ou, and J. C. 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