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• W2752884080 abstract "Changes in actin dynamics are communicated to the nucleus by members of the MRTF (myocardin related transcription factors) family of transcriptional coactivators. Upon signal induction G-actin liberates MRTF cofactors, which subsequently bind to and activate the transcription factor Serum Response Factor (SRF). SRF target genes in turn include numerous structural and regulatory components of the actin cytoskeleton as well as cytoskeleton-associated proteins involved in adhesion and cell motility. Moreover MRTFs are implicated in epithelial-mesenchymal transition (EMT), a developmentally regulated process which is also involved in tumor progression. EMT is characterized by dissociation of cell-cell contacts and a morphological conversion towards unpolarized motile cells. Together, these findings suggest a role of actin-MAL-SRF signaling in cell motility. I analyzed the migratory effects of actin-MAL mediated transcription in non-invasive cell lines and examined the regulation of MAL during EMT. An unbiased microarray screen identified Serpine1 (Pai-1) and the cytoskeleton-associated genes Four-and-a-half LIM domains 1 (Fhl1), Plakophilin 2 (Pkp2), Integrin α5 (Itga5) and Epithelial Protein Lost in Neoplasm α (Eplin-α) as novel G-actin regulated targets. I confirmed their transcriptional induction by quantitative RT-PCR. Moreover, retroviral infection with constitutively active, dominant negative and MAL knockdown constructs established these genes as MAL targets. The SRF responsive elements of Pkp2 and Eplin-α could be identified by chromatin IP and luciferase reporter assays. Functionally, I showed that ectopic expression of active MAL impairs the migration of mesenchymal NIH 3T3 fibroblasts and epithelial EpRas cells in wound healing and Boyden chamber assays. Conversely, dominant negative constructs and partial knockdown of MAL enhanced motility in these non-invasive cells. I next asked how G-actin regulated cytoskeleton-associated targets are involved in the antimigratory function of MAL in non-invasive epithelial and mesenchymal cells. Knockdown of Integrin α5 and Plakophilin 2 (Pkp2) enhanced cell migration of fibroblasts, whereas Pkp2 and Fhl1 knockdown increased epithelial cell motility. In addition the reduced migration of epithelial cells stably expressing active MAL was partially restored by knockdown of either Pkp2 or Fhl1, or by double knockdown. Overall I concluded that MAL is implicated in antimigratory responses through upregulation of the cytoskeleton-associated proteins Integrin α5, PKP2 and FHL1 in non-invasive cells. We have recently demonstrated that MAL is activated during EMT and calcium-dependent disassembly of epithelial junctions. I showed that MAL is upregulated on both mRNA and protein level upon EMT induction whereas MRTF-B expression was essentially unaffected. The microRNA miR-1 appeared to be involved in the regulation of MAL expression by binding to a highly conserved binding site in the MAL 3’UTR. Further analyses will have to determine how miR-1 contributes to the regulation of MAL during EMT induction. My findings that MAL exhibits antimigratory functions in non-invasive cell lines is contrasted by the previously described requirement of MRTFs for motility and invasion of metastatic breast cancer cells. To address the underlying discrepancies, I first reproduced the antimigratory effect of a partial Mrtf knockdown in the highly invasive MDA-MB-231 cells. In addition I could show that MAL enhances migration of invasive EpRasXT cells that have undergone EMT, which is in marked contrast to the antimigratory effect of MAL in the corresponding non-invasive epithelial EpRas cells. These findings demonstrated a fundamentally different migratory function of MRTFs in invasive and non-invasive cells. Based on these results, I hypothesize that MAL activity directly correlates with adhesive strength through its numerous cytoskeleton-associated targets. As migration speed shows a biphasic dependence on the adhesiveness I speculate that increasing MAL signaling activity in non-invasive cell lines with an already large repertoire of cytoskeletal and adhesive components reduces motility. Conversely, weakly adherent cells respond with reduced motility to decreased MAL signaling." @default.
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• W2752884080 date "2011-01-01" @default.
• W2752884080 modified "2023-09-23" @default.
• W2752884080 title "The role of the transcriptional coactivator MAL and its target genes in cell motility and EMT" @default.
• W2752884080 hasPublicationYear "2011" @default.
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