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Molecular and Cellular Biology, August 2004, p. 6824-6836, Vol. 24, No. 15
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.15.6824-6836.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Cross Talk between Retinoic Acid Signaling and Transcription Factor GATA-2

Shinobu Tsuzuki,1,2 Kenji Kitajima,3 Toru Nakano,3 Annegret Glasow,4 Arthur Zelent,4 and Tariq Enver1,5*

Section of Gene Function and Regulation, Institute of Cancer Research, London SW3 6JB,1 Leukemia Research Fund Centre, Institute of Cancer Research, London SW3 6JB,4 MRC Molecular Hematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, United Kingdom,5 Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya 464-8681,2 Department of Molecular Cell Biology, Research Institute for Microbial Diseases, Osaka University, Suita 565-0871, Japan3

Received 13 January 2004/ Returned for modification 12 March 2004/ Accepted 19 April 2004

All-trans-retinoic acid (RA) stimulates differentiation of normal hematopoietic progenitors and acute myeloid leukemia cells. GATA-2 is a transcription factor expressed in early progenitor cells and implicated in the control of the fate of hematopoietic stem cells and progenitor cells. We have investigated the possibility that the GATA and nuclear hormone receptor pathways are functionally linked through direct protein-protein interaction. Here we demonstrate that in human myeloid KG1 cells, RA receptor alpha (RAR{alpha}), the major RAR expressed in hematopoietic cells, associates with GATA-2. This association is mediated by the zinc fingers of GATA-2 and the DNA-binding domain of RAR{alpha}. As a consequence of this interaction, RAR{alpha} is tethered to the DNA sites that are recognized and bound by GATA-2, and the transcriptional activity of GATA-2 becomes RA responsive. The RA responsiveness of GATA-dependent transcription is eliminated by expression of either a dominant negative form of RAR{alpha} or a GATA-2 mutant that fails to interact with RAR{alpha}. Overexpression of RXR{alpha} inhibits RAR{alpha} binding to the GATA-2-DNA complex, thus resulting in attenuation of the effects of RAR{alpha} on GATA-2 activity. In addition, inhibition by RA of GATA-2-dependent hematopoietic colony formation in an embryonic stem cell model of hematopoietic differentiation provided biological evidence for functional cross talk between RA and GATA-2-dependent pathways.

* Corresponding author. Mailing address: MRC, MHU, WIMM, John Radcliffe Hospital, Headington, Oxford, United Kingdom. Phone: 44 (0)1865 222412. Fax: 44 (0)1865 222449. E-mail: tenver{at}gwmail.jr2.ox.ac.uk.

Molecular and Cellular Biology, August 2004, p. 6824-6836, Vol. 24, No. 15
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.15.6824-6836.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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