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

ABSTRACT 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.

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ErbB4 signals Neuregulin1-stimulated cell proliferation and c-fos gene expression through phosphorylation of serum response factor by mitogen-activated protein kinase cascade

Molecular and Cellular Biochemistry ◽

10.1007/s11010-009-0375-z ◽

2010 ◽

Vol 339 (1-2) ◽

pp. 119-125 ◽

Cited By ~ 12

Author(s):

Ko Eto ◽

Asuka Hommyo ◽

Rie Yonemitsu ◽

Shin-ichi Abe

Keyword(s):

Gene Expression ◽

Cell Proliferation ◽

Protein Kinase ◽

Serum Response Factor ◽

Mitogen Activated Protein Kinase ◽

Response Factor ◽

Mitogen Activated Protein ◽

Kinase Cascade ◽

Serum Response ◽

Protein Kinase Cascade

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Platelet-derived Growth Factor-BB-mediated Activation of Akt Suppresses Smooth Muscle-specific Gene Expression through Inhibition of Mitogen-activated Protein Kinase and Redistribution of Serum Response Factor

Journal of Biological Chemistry ◽

10.1074/jbc.m305991200 ◽

2003 ◽

Vol 278 (41) ◽

pp. 39830-39838 ◽

Cited By ~ 45

Author(s):

Nihal Kaplan-Albuquerque ◽

Chrystelle Garat ◽

Christina Desseva ◽

Peter L. Jones ◽

Raphael A. Nemenoff

Keyword(s):

Gene Expression ◽

Smooth Muscle ◽

Growth Factor ◽

Serum Response Factor ◽

Mitogen Activated Protein Kinase ◽

Platelet Derived Growth Factor ◽

Specific Gene ◽

Response Factor ◽

Mitogen Activated Protein ◽

Serum Response

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Four isoforms of serum response factor that increase or inhibit smooth-muscle-specific promoter activity

Biochemical Journal ◽

10.1042/bj3450445 ◽

2000 ◽

Vol 345 (3) ◽

pp. 445-451 ◽

Cited By ~ 22

Author(s):

Paul R. KEMP ◽

James C. METCALFE

Keyword(s):

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Serum Response Factor ◽

Muscle Cells ◽

Dominant Negative ◽

C2c12 Cells ◽

Specific Gene ◽

Response Factor ◽

Transactivation Domain ◽

Serum Response

Serum response factor (SRF) is a key transcriptional activator of the c-fos gene and of muscle-specific gene expression. We have identified four forms of the SRF coding sequence, SRF-L (the previously identified form), SRF-M, SRF-S and SRF-I, that are produced by alternative splicing. The new forms of SRF lack regions of the C-terminal transactivation domain by splicing out of exon 5 (SRF-M), exons 4 and 5 (SRF-S) and exons 3, 4 and 5 (SRF-I). SRF-M is expressed at similar levels to SRF-L in differentiated vascular smooth-muscle cells and skeletal-muscle cells, whereas SRF-L is the predominant form in many other tissues. SRF-S expression is restricted to vascular smooth muscle and SRF-I expression is restricted to the embryo. Transfection of SRF-L and SRF-M into C2C12 cells showed that both forms are transactivators of the promoter of the smooth-muscle-specific gene SM22α, whereas SRF-I acted as a dominant negative form of SRF.

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New Role for Serum Response Factor in Postnatal Skeletal Muscle Growth and Regeneration via the Interleukin 4 and Insulin-Like Growth Factor 1 Pathways

Molecular and Cellular Biology ◽

10.1128/mcb.00138-06 ◽

2006 ◽

Vol 26 (17) ◽

pp. 6664-6674 ◽

Cited By ~ 53

Author(s):

Claude Charvet ◽

Christophe Houbron ◽

Ara Parlakian ◽

Julien Giordani ◽

Charlotte Lahoute ◽

...

Keyword(s):

Gene Expression ◽

Skeletal Muscle ◽

Growth Factor ◽

Serum Response Factor ◽

Muscle Growth ◽

Interleukin 4 ◽

Specific Gene ◽

Response Factor ◽

Insulin Like Growth Factor ◽

Serum Response

ABSTRACT Serum response factor (SRF) is a crucial transcriptional factor for muscle-specific gene expression. We investigated SRF function in adult skeletal muscles, using mice with a postmitotic myofiber-targeted disruption of the SRF gene. Mutant mice displayed severe skeletal muscle mass reductions due to a postnatal muscle growth defect resulting in highly hypotrophic adult myofibers. SRF-depleted myofibers also failed to regenerate following injury. Muscles lacking SRF had very low levels of muscle creatine kinase and skeletal alpha-actin (SKA) transcripts and displayed other alterations to the gene expression program, indicating an overall immaturity of mutant muscles. This loss of SKA expression, together with a decrease in beta-tropomyosin expression, contributed to myofiber growth defects, as suggested by the extensive sarcomere disorganization found in mutant muscles. However, we observed a downregulation of interleukin 4 (IL-4) and insulin-like growth factor 1 (IGF-1) expression in mutant myofibers which could also account for their defective growth and regeneration. Indeed, our demonstration of SRF binding to interleukin 4 and IGF-1 promoters in vivo suggests a new crucial role for SRF in pathways involved in muscle growth and regeneration.

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Alternative splicing and nonsense-mediated mRNA decay regulate gene expression of serum response factor

Gene ◽

10.1016/j.gene.2007.06.008 ◽

2007 ◽

Vol 400 (1-2) ◽

pp. 131-139 ◽

Cited By ~ 13

Author(s):

Xiaomin Zhang ◽

Gohar Azhar ◽

Chris Huang ◽

Cunqi Cui ◽

Ying Zhong ◽

...

Keyword(s):

Gene Expression ◽

Alternative Splicing ◽

Mrna Decay ◽

Serum Response Factor ◽

Response Factor ◽

Regulate Gene Expression ◽

Nonsense Mediated Mrna Decay ◽

Serum Response ◽

Regulate Gene

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Different regulatory sequences control creatine kinase-M gene expression in directly injected skeletal and cardiac muscle.

Molecular and Cellular Biology ◽

10.1128/mcb.13.2.1264 ◽

1993 ◽

Vol 13 (2) ◽

pp. 1264-1272 ◽

Cited By ~ 61

Author(s):

C K Vincent ◽

A Gualberto ◽

C V Patel ◽

K Walsh

Keyword(s):

Gene Expression ◽

Skeletal Muscle ◽

Creatine Kinase ◽

Cardiac Muscle ◽

Serum Response Factor ◽

Sequence Motif ◽

Regulatory Sequences ◽

Response Factor ◽

Specific Expression ◽

Serum Response

Regulatory sequences of the M isozyme of the creatine kinase (MCK) gene have been extensively mapped in skeletal muscle, but little is known about the sequences that control cardiac-specific expression. The promoter and enhancer sequences required for MCK gene expression were assayed by the direct injection of plasmid DNA constructs into adult rat cardiac and skeletal muscle. A 700-nucleotide fragment containing the enhancer and promoter of the rabbit MCK gene activated the expression of a downstream reporter gene in both muscle tissues. Deletion of the enhancer significantly decreased expression in skeletal muscle but had no detectable effect on expression in cardiac muscle. Further deletions revealed a CArG sequence motif at position -179 within the promoter that was essential for cardiac-specific expression. The CArG element of the MCK promoter bound to the recombinant serum response factor and YY1, transcription factors which control expression from structurally similar elements in the skeletal actin and c-fos promoters. MCK-CArG-binding activities that were similar or identical to serum response factor and YY1 were also detected in extracts from adult cardiac muscle. These data suggest that the MCK gene is controlled by different regulatory programs in adult cardiac and skeletal muscle.

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