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.
Descot
Arnaud
A
Max Planck Institute of Biochemistry, Department of Molecular Biology, Martinsried, Germany.
Rex-Haffner
Monika
M
Courtois
Geneviève
G
Bluteau
Dominique
D
Menssen
Antje
A
Mercher
Thomas
T
Bernard
Olivier A
OA
Treisman
Richard
R
Posern
Guido
G
D000199:Actins / Q000378:metabolism; D000818:Animals; D051766:Early Growth Response Protein 1 / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D026362:Serum Response Factor / Q000378:metabolism*; D015398:Signal Transduction; D050801:Ternary Complex Factors / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D000199:Actins; D051766:Early Growth Response Protein 1; C532421:OTT-MAL fusion protein, human; D015514:Oncogene Proteins, Fusion; D016760:Proto-Oncogene Proteins c-fos; D026362:Serum Response Factor; D050801:Ternary Complex Factors; D048049:Extracellular Signal-Regulated MAP Kinases; D020742:rhoA GTP-Binding Protein