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Mol. Cell. Biol. doi:10.1128/MCB.00303-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

OTT-MAL is a deregulated activator of SRF-dependent gene expression

Department of Molecular Biology, Max-Planck-Institute of Biochemistry, 82152 Martinsried, Germany; INSERM E0210, Hopital Necker, 75743 Paris, France; Transcription Laboratory, Cancer Research UK London Research Institute, London WC2A 3PX, United Kingdom

^* To whom correspondence should be addressed. Email: posern{at}biochem.mpg.de.

	Abstract

The OTT-MAL/RBM15-MKL1 fusion protein is the result of the recurrent translocation t(1;22) in acute megakaryocytic leukaemia in infants. How it contributes to the malignancy is unknown. The 3' fusion partner, MAL/MKL1/MRTF-A, is a transcriptional coactivator of serum response factor (SRF). MAL plays a key role in regulated gene expression depending on Rho family GTPases and G-actin. Here we demonstrate that OTT-MAL is a constitutive activator of SRF and target gene expression. This requires the SRF binding motif and the MAL-derived transactivation domain. OTT-MAL localises to the nucleus and is not regulated by upstream signalling. OTT-MAL deregulation reflects its independence from control by G-actin, which fails to interact with OTT-MAL in co-immunoprecipitation experiments. Regulation cannot be restored by re-introduction of the entire MAL N-terminus into the fusion protein. OTT-MAL also caused a delayed induction of the MAL-independent, TCF-dependent target genes c-fos and egr-1, and the MAPK/Erk pathway. When tested in heterologous tissue culture systems, however, we observed considerable anti-proliferative effects of OTT-MAL. Our data suggest that the deregulated activation of MAL-dependent and -independent promoters results in tissue-specific functions of OTT-MAL.