MRTF/SRF-dependent transcriptional regulation for bleb-associated cell invasion and entosis

Non-apoptotic plasma membrane blebbing occurs during cell motility and tumor spread in several human malignancies. Bleb dynamics are regulated through rearrangement of the cortical actin cytoskeleton and its associated proteins. Our previous studies reported the importance of plasma membrane blebbin...

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Bibliographic Details
Main Author: Soto Hinojosa, Laura
Contributors: Grosse, Robert (Prof. Dr.) (Thesis advisor)
Format: Dissertation
Language:English
Published: Philipps-Universität Marburg 2019
Pharmakologisches Institut
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Summary:Non-apoptotic plasma membrane blebbing occurs during cell motility and tumor spread in several human malignancies. Bleb dynamics are regulated through rearrangement of the cortical actin cytoskeleton and its associated proteins. Our previous studies reported the importance of plasma membrane blebbing by the formin mDia1 in providing the driving force for entotic invasion of one cell into its neighbouring cell. Entosis is a form of homotypic cell-in-cell invasion, in which low cellular adhesion induces ROCK- and actomyosin-dependent invasion. The physiological consequences of this process are not well-understood. Entotic invasion has been suggested to induce tumor promoting effects, while other studies supported a tumor suppressor role. Although the molecular requirements and actin-binding proteins controlling bleb dynamics are well characterized, the importance of a potential transcriptional regulation underlying sustained, long-term blebbing as observed during cancer cell or entotic invasion has not been studied. Given the direct association between the Serum Response Factor (SRF) coactivator Myocardin-Related Transcription Factor (MRTF-A) and actin dynamics, we addressed the impact of the MRTF/SRF transcriptional pathway for plasma membrane blebbing and bleb-associated entotic invasion. In this study, we find that cortical contractility during plasma membrane blebbing is tightly associated to dynamic MRTF cytoplasmic-nuclear shuttling. Our findings reveal that not only the dynamics of plasma membrane blebs depend on MRTF/SRF, but also entotic invasion. Interestingly, we found that MRTF/SRF-dependent upregulation of the metastasis associated ERM protein Ezrin is fundamental for non-apoptotic blebbing and entotic invasion. Thus, our results highlight a novel mechanism, by which the actin-dependent transcription factor MRTF controls Ezrin expression to facilitate bleb-associated invasive motility. These findings may have important implications in understanding invasive motility as well as for future concepts targeting metastasis.
Physical Description:132 Pages
DOI:https://doi.org/10.17192/z2019.0289