TY - JOUR
T1 - OTT-MAL is a deregulated activator of serum response factor-dependent gene expression
AU - Descot, Arnaud
AU - Rex-Haffner, Monika
AU - Courtois, Geneviève
AU - Bluteau, Dominique
AU - Menssen, Antje
AU - Mercher, Thomas
AU - Bernard, Olivier A.
AU - Treisman, Richard
AU - Posern, Guido
PY - 2008/10/1
Y1 - 2008/10/1
N2 - The OTT-MAL/RBM15-MKL1 fusion protein is the result of the recurrent translocation t(1;22) in acute megakaryocytc 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.
AB - The OTT-MAL/RBM15-MKL1 fusion protein is the result of the recurrent translocation t(1;22) in acute megakaryocytc 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.
UR - http://www.scopus.com/inward/record.url?scp=53549117148&partnerID=8YFLogxK
U2 - 10.1128/MCB.00303-08
DO - 10.1128/MCB.00303-08
M3 - Article
C2 - 18710951
AN - SCOPUS:53549117148
SN - 0270-7306
VL - 28
SP - 6171
EP - 6181
JO - Molecular and Cellular Biology
JF - Molecular and Cellular Biology
IS - 20
ER -