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

被引：36

作者：

Descot, Arnaud ^{[1
]}

Rex-Haffner, Monika ^{[1
]}

Courtois, Genevieve ^{[2
]}

Bluteau, Dominique ^{[2
]}

Menssen, Antje ^{[1
]}

Mercher, Thomas ^{[2
]}

Bernard, Olivier A. ^{[2
]}

Treisman, Richard ^{[3
]}

Posern, Guido ^{[1
]}

机构：

[1] Max Planck Inst Biochem, Dept Mol Biol, D-82152 Martinsried, Germany

[2] Hop Necker Enfants Malad, INSERM, E0210, F-75743 Paris, France

[3] Canc Res UK London Res Inst, Transcript Lab, London WC2A 3PX, England

来源：

MOLECULAR AND CELLULAR BIOLOGY | 2008年 / 28卷 / 20期

关键词：

D O I：

10.1128/MCB.00303-08

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：6171 / 6181

页数：11

共 32 条

[1] Activation of SRF-regulated chromosomal templates by Rho-family GTPases requires a signal that also induces H4 hyperacetylation [J].

Alberts, AS ;

Geneste, O ;

Treisman, R .

CELL, 1998, 92 (04) :475-487

[2] A conserved structural motif reveals the essential transcriptional repression function of Spen proteins and their role in developmental signaling [J].

Ariyoshi, M ;

Schwabe, JWR .

GENES & DEVELOPMENT, 2003, 17 (15) :1909-1920

[3]

CARROLL A, 1991, BLOOD, V78, P748

[4] Megakaryoblastic leukemia 1, a potent transcriptional coactivator for serum response factor (SRF), is required for serum induction of SRF target genes [J].

Cen, B ;

Selvaraj, A ;

Burgess, RC ;

Hitzler, JK ;

Ma, ZG ;

Morris, SW ;

Prywes, R .

MOLECULAR AND CELLULAR BIOLOGY, 2003, 23 (18) :6597-6608

[5] split ends, a new component of the Drosophila EGF receptor pathway, regulates development of midline glial cells [J].

Chen, FL ;

Rebay, I .

CURRENT BIOLOGY, 2000, 10 (15) :943-946

[6] Interaction of the Epstein-Barr virus mRNA export factor EB2 with human spen proteins SHARP, OTT1, and a novel member of the family, OTT3, links spen proteins with splicing regulation and mRNA export [J].

Hiriart, E ;

Gruffat, H ;

Buisson, M ;

Mikaelian, I ;

Keppler, S ;

Meresse, P ;

Mercher, T ;

Bernard, OA ;

Sergeant, A ;

Manet, E .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (44) :36935-36945

[7] Characterization of the split ends-like gene spenito reveals functional antagonism between SPOC family members during drosophila eye development [J].

Jemc, Jennifer ;

Rebay, Ilaria .

GENETICS, 2006, 173 (01) :279-286

[8]

Kuang B, 2000, DEVELOPMENT, V127, P1517

[9] Regulation of marginal zone B cell development by MINT, a suppressor of Notch/RBP-J signaling pathway [J].

Kuroda, K ;

Han, H ;

Tani, S ;

Tanigaki, K ;

Tun, T ;

Furukawa, T ;

Taniguchi, Y ;

Kurooka, H ;

Hamada, Y ;

Toyokuni, S ;

Honjo, T .

IMMUNITY, 2003, 18 (02) :301-312

[10] Rbm15 modulates notch-induced transcriptional activation and affects myeloid differentiation [J].

Ma, Xianyong ;

Renda, Matthew J. ;

Wang, Lin ;

Cheng, Ee-chun ;

Niu, Chao ;

Morris, Stephan W. ;

Chi, Andrew S. ;

Krause, Diane S. .

MOLECULAR AND CELLULAR BIOLOGY, 2007, 27 (08) :3056-3064

← 1 2 3 4 →