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Molecular and Cellular Biology, April 2002, p. 2632-2641, Vol. 22, No. 8
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.8.2632-2641.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Direct Channeling of Retinoic Acid between Cellular Retinoic Acid-Binding Protein II and Retinoic Acid Receptor Sensitizes Mammary Carcinoma Cells to Retinoic Acid-Induced Growth Arrest

Anuradha S. Budhu and Noa Noy*

Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853

Received 10 September 2001/ Returned for modification 11 October 2001/ Accepted 8 January 2002

Cellular retinoic acid-binding protein II (CRABP-II) is an intracellular lipid-binding protein that associates with retinoic acid with a subnanomolar affinity. We previously showed that CRABP-II enhances the transcriptional activity of the nuclear receptor with which it shares a common ligand, namely, the retinoic acid receptor (RAR), and we suggested that it may act by delivering retinoic acid to this receptor. Here, the mechanisms underlying the effects of CRABP-II on the transcriptional activity of RAR and the functional consequences of these effects were studied. We show that CRABP-II, a predominantly cytosolic protein, massively undergoes nuclear localization upon binding of retinoic acid; that it interacts with RAR in a ligand-dependent fashion; and that, in the presence of retinoic acid, the CRABP-II-RAR complex is a short-lived intermediate. The data establish that potentiation of the transcriptional activity of RAR stems directly from the ability of CRABP-II to channel retinoic acid to the receptor. We demonstrate further that overexpression of CRABP-II in MCF-7 mammary carcinoma cells dramatically enhances their sensitivity to retinoic acid-induced growth inhibition. Conversely, diminished expression of CRABP-II renders these cells retinoic acid resistant. Taken together, the data unequivocally establish the function of CRABP-II in modulating the RAR-mediated biological activities of retinoic acid.

* Corresponding author. Mailing address: 225 Savage Hall, Cornell University, Ithaca, NY 14853. Phone: (607) 255-2490. Fax: (607) 255-1033. E-mail: nn14{at}cornell.edu.

Molecular and Cellular Biology, April 2002, p. 2632-2641, Vol. 22, No. 8
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.8.2632-2641.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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