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      Epithelial Protein Lost in Neoplasm α (Eplin-α) is transcriptionally regulated by G-actin and MAL/MRTF coactivators

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          Abstract

          Epithelial Protein Lost in Neoplasm α is a novel cytoskeleton-associated tumor suppressor whose expression inversely correlates with cell growth, motility, invasion and cancer mortality. Here we show that Eplin-α transcription is regulated by actin-MAL-SRF signalling. Upon signal induction, the coactivator MAL/MRTF is released from a repressive complex with monomeric actin, binds the transcription factor SRF and activates target gene expression. In a transcriptome analysis with a combination of actin binding drugs which specifically and differentially interfere with the actin-MAL complex (Descot et al., 2009), we identified Eplin to be primarily controlled by monomeric actin. Further analysis revealed that induction of the Eplin-α mRNA and its promoter was sensitive to drugs and mutant actins which stabilise the repressive actin-MAL complex. In contrast, the Eplin-β isoform remained unaffected. Knockdown of MRTFs or dominant negative MAL which inhibits SRF-mediated transcription impaired Eplin-α expression. Conversely, constitutively active mutant actins and MAL induced Eplin-α. MAL and SRF were bound to a consensus SRF binding site of the Eplin-α promoter; the recruitment of MAL to this region was enhanced severalfold upon induction. The tumor suppressor Eplin-α is thus a novel cytoskeletal target gene transcriptionally regulated by the actin-MAL-SRF pathway, which supports a role in cancer biology.

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          Most cited references 14

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          Actin' together: serum response factor, its cofactors and the link to signal transduction.

          The vast diversity of cellular types and behaviours is mainly the result of combinatorial interactions between a limited number of transcription factors and cellular signalling pathways whose activity is stringently controlled by developmental, cellular and extracellular cues. Studies of serum response factor (SRF) have provided a paradigm for such interactions for some years. Recent advances have shown that two families of SRF cofactors, the ternary complex factors (TCFs) and the myocardin-related transcription factors (MTRFs), are regulated by separate signalling pathways and thereby control SRF target genes differentially. The actin cytoskeleton is both an upstream regulator of MRTF activity, with monomeric actin directly acting as a signal transducer, and a downstream effector, because of the many cytoskeletal target genes. Here we discuss how the competition among cofactors might integrate these distinct signalling pathways into a specific transcriptional response and biological function.
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            Myocardin-Related Transcription Factors and SRF are required for cytoskeletal dynamics, invasion and experimental metastasis

            Rho GTPases control cytoskeletal dynamics through cytoplasmic effectors, and regulate transcriptional activation by the Myocardin Related Transcription Factors (MRTFs), coactivators for Serum Response Factor (SRF). We used RNAi to investigate the contribution of the MRTF-SRF pathway to cytoskeletal dynamics in MDA-MB-231 breast carcinoma and B16F2 melanoma cells, where basal MRTF-SRF activity is Rho-dependent. Depletion of MRTFs or SRF reduces cell adhesion, spreading, invasion and motility in culture, without affecting proliferation or inducing apoptosis; MRTF-depleted tumor cell xenografts exhibit reduced cell motility but proliferate normally. MRTF- and SRF-depleted tumor cells fail to colonise the lung from the bloodstream, being unable to persist following their initial arrival at the lung. Only a few genes exhibit MRTF-dependent expression in both cell lines. Two of these, MYH9 (MLC2) and MYL9 (NMHCIIa), are also required for invasion and lung colonisation. Conversely, expression of an activated MRTF increases lung colonisation by poorly metastatic B16F0 cells. Actin-based cell behaviour and experimental metastasis thus requires Rho-dependent nuclear signalling through the MRTF-SRF network.
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              Myocardin and ternary complex factors compete for SRF to control smooth muscle gene expression.

              Smooth muscle cells switch between differentiated and proliferative phenotypes in response to extracellular cues, but the transcriptional mechanisms that confer such phenotypic plasticity remain unclear. Serum response factor (SRF) activates genes involved in smooth muscle differentiation and proliferation by recruiting muscle-restricted cofactors, such as the transcriptional coactivator myocardin, and ternary complex factors (TCFs) of the ETS-domain family, respectively. Here we show that growth signals repress smooth muscle genes by triggering the displacement of myocardin from SRF by Elk-1, a TCF that acts as a myogenic repressor. The opposing influences of myocardin and Elk-1 on smooth muscle gene expression are mediated by structurally related SRF-binding motifs that compete for a common docking site on SRF. A mutant smooth muscle promoter, retaining responsiveness to myocardin and SRF but defective in TCF binding, directs ectopic transcription in the embryonic heart, demonstrating a role for TCFs in suppression of smooth muscle gene expression in vivo. We conclude that growth and developmental signals modulate smooth muscle gene expression by regulating the association of SRF with antagonistic cofactors.
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                Author and article information

                Journal
                Mol Cancer
                Molecular Cancer
                BioMed Central
                1476-4598
                2010
                17 March 2010
                : 9
                : 60
                Affiliations
                [1 ]AG Regulation of Gene Expression, Department of Molecular Biology, Max-Planck-Institute of Biochemistry, D-82152 Martinsried, Germany
                [2 ]Institute of Medical Microbiology and Immunology, Technical University of Munich, D-81675 München, Germany
                Article
                1476-4598-9-60
                10.1186/1476-4598-9-60
                2848193
                20236507
                Copyright ©2010 Leitner et al; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Categories
                Short communication

                Oncology & Radiotherapy

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