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J. Biol. Chem., Vol. 281, Issue 20, 14465-14473, May 19, 2006

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Cytoplasmic Function of Mutant Promyelocytic Leukemia (PML) and PML-Retinoic Acid Receptor-^*

Cristian Bellodi, Karin Kindle^¶, Francesca Bernassola^||, David Dinsdale, Andrea Cossarizza, Gerry Melino, David Heery^¶, and Paolo Salomoni¹

From the Medical Research Council Toxicology Unit, Leicester LE1 9HN, United Kingdom, ^¶School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, United Kingdom, ^||IDI-IRCCS Biochemistry Laboratory, Department of Experimental Medicine, University of Rome Tor Vergata, Rome 00133, Italy, and Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena 41100, Italy

The promyelocytic leukemia (PML) tumor suppressor of acute promyelocytic leukemia (APL) regulates major apoptotic and growth-suppressive pathways. In APL, PML is involved in a chromosomal translocation generating the PML-retinoic acid receptor- (RAR) fusion protein. Two missense mutations in the remaining PML alleles have been identified, which give rise to a truncated cytoplasmic PML protein (Mut PML). APL patients carrying these mutations display resistance to retinoic acid (RA) and very poor prognosis. Here we show that Mut PML associates with the cytoplasmic regions we refer to as PML-cytoplasmic bodies (PML-CBs). Mut PML interacts with PML-RAR in PML-CB and potentiates PML-RAR-mediated inhibition of RA-dependent transcription. Remarkably, Mut PML stabilizes PML-RAR and inhibits differentiation induced by pharmacological doses of RA. A mutant form of PML-RAR that accumulates in the cytoplasm inhibits RA-dependent transcription and differentiation, thus suggesting that cytoplasmic localization of PML-RAR may contribute to transformation. Finally, we show that the bcr3 PML-RAR form is predominantly cytoplasmic and accumulates in PML-CBs. Taken together, these findings reveal novel insights into the molecular mechanisms contributing to APL.

Received for publication, January 17, 2006

^* This work was supported by the Medical Research Council. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ To whom correspondence should be addressed. Tel.: 44-116-2525568; Fax: 44-116-2525616; E-mail: ps90{at}le.ac.uk.

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