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Molecular and Cellular Biology, March 2004, p. 2423-2443, Vol. 24, No. 6
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.6.2423-2443.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

A Novel Retinoic Acid-Responsive Element Regulates Retinoic Acid-Induced BLR1 Expression

Jianrong Wang and Andrew Yen*

Department of Biomedical Sciences, Cornell University, Ithaca, New York 14853

Received 14 July 2003/ Returned for modification 27 August 2003/ Accepted 10 December 2003

The mechanism of action of retinoic acid (RA) is of broad relevance to cell and developmental biology, nutrition, and cancer chemotherapy. RA is known to induce expression of the Burkitt's lymphoma receptor 1 (BLR1) gene which propels RA-induced cell cycle arrest and differentiation of HL-60 human myeloblastic leukemia cells, motivating the present analysis of transcriptional regulation of blr1 expression by RA. The RA-treated HL-60 cells used here expressed all RA receptor (RAR) and retinoid X receptor (RXR) subtypes (as detected by Northern analysis) except RXR{gamma}. Treatment with RAR- and RXR-selective ligands showed that RAR{alpha} synergized with RXR{alpha} to transcriptionally activate blr1 expression. A 5'-flanking region capable of supporting RA-induced blr1 activation in HL-60 cells was found to contain a 205-bp sequence in the distal portion that was necessary for transcriptional activation by RA. Within this sequence DNase I footprinting revealed that RA induced binding of a nuclear protein complex to an element containing two GT boxes. Electromobility shift assays (EMSAs) and supershift assays showed that this element bound recombinant RAR{alpha} and RXR{alpha}. Without RA there was neither complex binding nor transcriptional activation. Both GT boxes were needed for binding the complex, and mutation of either GT box caused the loss of transcriptional activation by RA. The ability of this cis-acting RAR-RXR binding element to activate transcription in response to RA also depended on downstream sequences where an octamer transcription factor 1 (Oct1) site and a nuclear factor of activated T cells (NFATc) site between this element and the transcriptional start, as well as a cyclic AMP response element binding factor (CREB) site between the transcriptional start and first exon of the blr1 gene, were necessary. Each of these sites bound its corresponding transcription factor. A transcription factor-transcription factor binding array analysis of nuclear lysate from RA-treated cells indicated several prominent RAR{alpha} binding partners; among these, Oct1, NFATc3, and CREB2 were identified by competition EMSA and supershift and chromatin immunoprecipitation assays as components of the complex. RA upregulated expression of these three factors. In sum the results of the present study indicate that RA-induced expression of blr1 expression depends on a novel RA response element. This cis-acting element approximately 1 kb upstream of the transcriptional start consists of two GT boxes that bind RAR and RXR in a nuclear protein complex that also contains Oct1, NFATc3, and CREB2 bound to their cognate downstream consensus binding sites.

* Corresponding author. Mailing address: Department of Biomedical Sciences, T4-008 VRT, Cornell University, Ithaca, NY 14853. Phone: (607) 253-3354. Fax: (607) 253-3317. E-mail: ay13{at}cornell.edu.

Molecular and Cellular Biology, March 2004, p. 2423-2443, Vol. 24, No. 6
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.6.2423-2443.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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