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PMID: 18710951 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

OTT-MAL is a deregulated activator of serum response factor-dependent gene expression.

Molecular and cellular biology ·Vol. 28 ·No. 20 ·2008-10-00 ·Pages 6171-81

Descot A, Rex-Haffner M, Courtois G, Bluteau D, Menssen A, Mercher T, Bernard OA, Treisman R, Posern G

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.

MeSH Terms
Actins/metabolism Animals Early Growth Response Protein 1/genetics Extracellular Signal-Regulated MAP Kinases/metabolism Gene Expression Regulation HeLa Cells Humans Intracellular Space/metabolism Mice NIH 3T3 Cells Oncogene Proteins, Fusion/chemistry,metabolism Phosphorylation Protein Binding Protein Structure, Tertiary Protein Transport Proto-Oncogene Proteins c-fos/metabolism Serum Response Factor/metabolism Signal Transduction Ternary Complex Factors/metabolism rhoA GTP-Binding Protein/metabolism
Chemicals
Actins Early Growth Response Protein 1 OTT-MAL fusion protein, human Oncogene Proteins, Fusion Proto-Oncogene Proteins c-fos Serum Response Factor Ternary Complex Factors Extracellular Signal-Regulated MAP Kinases rhoA GTP-Binding Protein
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Descot Arnaud
Max Planck Institute of Biochemistry, Department of Molecular Biology, Martinsried, Germany.
Rex-Haffner Monika
Courtois Geneviève
Bluteau Dominique
Menssen Antje
Mercher Thomas
Bernard Olivier A
Treisman Richard
Posern Guido
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
1098-5549
DOI
10.1128/MCB.00303-08
Published
2008-10-00
Epub
2008-00-18
Pages
6171-81
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC2577437
Subset
IM
Grants
Cancer Research UK · United Kingdom
External Links
PubMed source DOI: 10.1128/MCB.00303-08 PMC Full Text View journal details
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