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Prepublished online as a Blood First Edition Paper on January 23, 2003; DOI 10.1182/blood-2002-10-3174.
Submitted October 21, 2002
Accepted January 16, 2003
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*
Department of Biochemistry & Molecular Biology, Medical College of Ohio, Toledo, OH, USA
* Corresponding author; email: mratnam{at}mco.edu.
Folate receptor (FR) type  is a promising target for therapeutic intervention in acute myelogenous leukemia (AML) owing particularly to its specific upregulation in AML cells by all-trans retinoic acid (ATRA) (Wang et al, 2000, Blood, 96:3529-3536; Pan et al, 2002, Blood, 100:594-602). 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 (EBS) elements and repression by upstream Ap-1-like elements, whose action required EBS. 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, downregulation 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 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 three RAR subtypes bind agonist.
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