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Molecular and Cellular Biology, October 2008, p. 6171-6181, Vol. 28, No. 20
0270-7306/08/$08.00+0     doi:10.1128/MCB.00303-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

OTT-MAL Is a Deregulated Activator of Serum Response Factor-Dependent Gene Expression {triangledown}

Arnaud Descot,1 Monika Rex-Haffner,1 Geneviève Courtois,2 Dominique Bluteau,2 Antje Menssen,1 Thomas Mercher,2 Olivier A. Bernard,2 Richard Treisman,3 and Guido Posern1*

Department of Molecular Biology, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany,1 INSERM E0210, Hôpital Necker, 75743 Paris, France,2 Transcription Laboratory, Cancer Research UK London Research Institute, London WC2A 3PX, United Kingdom3

Received 22 February 2008/ Returned for modification 2 June 2008/ Accepted 5 August 2008

The OTT-MAL/RBM15-MKL1 fusion protein is the result of the recurrent translocation t(1;22) in acute megakaryocytic leukemia 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 localizes to the nucleus and is not regulated by upstream signaling. OTT-MAL deregulation reflects its independence from control by G-actin, which fails to interact with OTT-MAL in coimmunoprecipitation experiments. Regulation cannot be restored by reintroduction of the entire MAL N terminus into the fusion protein. OTT-MAL also caused a delayed induction of the MAL-independent, ternary complex factor-dependent target genes c-fos and egr-1 and the mitogen-activated protein kinase/Erk pathway. With testing in heterologous tissue culture systems, however, we observed considerable antiproliferative 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.

* Corresponding author. Mailing address: Max Planck Institute of Biochemistry, Department of Molecular Biology, Am Klopferspitz 18, D-82152 Martinsried, Germany. Phone: 49-(0)89-8578-2877. Fax: 49-(0)89-8578-2454. E-mail: posern{at}biochem.mpg.de

{triangledown} Published ahead of print on 18 August 2008.

Molecular and Cellular Biology, October 2008, p. 6171-6181, Vol. 28, No. 20
0270-7306/08/$08.00+0     doi:10.1128/MCB.00303-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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