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J. Biol. Chem., Vol. 281, Issue 25, 17124-17133, June 23, 2006

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MOZ-TIF2 Alters Cofactor Recruitment and Histone Modification at the RAR2 Promoter

DIFFERENTIAL EFFECTS OF MOZ FUSION PROTEINS ON CBP- AND MOZ-DEPENDENT ACTIVATORS^*

Hilary M. Collins, Karin B. Kindle, Sachiko Matsuda, Colm Ryan, Philip J. F. Troke, Eric Kalkhoven¹, and David M. Heery²

From the School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, United Kingdom and the Department of Metabolic and Endocrine Diseases, University Medical Center Utrecht, Lundlaan 6, 3584 EA Utrecht, The Netherlands

MOZ-TIF2 and MOZ-CBP are leukemogenic fusion proteins associated with therapy-induced acute myeloid leukemia. These proteins are thought to subvert normal gene expression in differentiating hematopoietic progenitor cells. We have previously shown that MOZ-TIF2 inhibits transcription by CREB-binding protein (CBP)/p300-dependent activators such as nuclear receptors and p53. Here we have shown that MOZ-TIF2 associates with the RAR2 promoter in vivo, resulting in altered recruitment of CBP/p300, aberrant histone modification, and down-regulation of the RAR2 gene. In contrast, MOZ-TIF2 up-regulated transcription mediated by the MOZ/MYST3-dependent activator AML1/RUNX1. Both wild type MOZ and MOZ-TIF2 were found to colocalize with AML1, and MOZ-TIF2 was recruited to an AML1 target promoter. A MOZ-CBP fusion protein showed similar functions to MOZ-TIF2 in that it inhibited retinoic acid receptor-mediated transcription but enhanced AML1 reporter activation. Although it contains almost the entire CBP sequence, MOZ-CBP does not appear to associate with PML bodies. In summary, our results indicate that leukemogenic MOZ fusion proteins have differential effects on the activities of CBP-dependent and MOZ-dependent activators because of their ability to alter cofactor recruitment and chromatin modification at target promoters.

Received for publication, March 21, 2006

^* This work was supported in part by grants from Cancer Research UK and the Leukemia Research Fund and a Wellcome Senior Fellowship (to D. M. H.). 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.

¹ Supported by a fellowship from the Royal Netherlands Society for Arts and Sciences.

² To whom correspondence should be addressed. Tel.: 44-115-9515087; Fax: 44-115-8466249; E-mail: david.heery{at}nottingham.ac.uk.

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