OTT-MAL Is a Deregulated Activator of Serum Response Factor-Dependent Gene Expression
Copyright policy )OTT-MAL Is a Deregulated Activator of Serum Response Factor-Dependent Gene Expression
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.
- Max Planck Society Germany
- London Research Institute United Kingdom
- Max Planck Institute of Biochemistry Germany
- Necker-Enfants Malades Hospital France
- Assistance Publique -Hopitaux De Paris France
Serum Response Factor, Oncogene Proteins, Fusion, Intracellular Space, Ternary Complex Factors, Actins, Protein Structure, Tertiary, Mice, Protein Transport, Gene Expression Regulation, NIH 3T3 Cells, Animals, Humans, Phosphorylation, Extracellular Signal-Regulated MAP Kinases, rhoA GTP-Binding Protein, Proto-Oncogene Proteins c-fos, Early Growth Response Protein 1, HeLa Cells, Protein Binding, Signal Transduction
Serum Response Factor, Oncogene Proteins, Fusion, Intracellular Space, Ternary Complex Factors, Actins, Protein Structure, Tertiary, Mice, Protein Transport, Gene Expression Regulation, NIH 3T3 Cells, Animals, Humans, Phosphorylation, Extracellular Signal-Regulated MAP Kinases, rhoA GTP-Binding Protein, Proto-Oncogene Proteins c-fos, Early Growth Response Protein 1, HeLa Cells, Protein Binding, Signal Transduction
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