Regulation and function of nuclear actin polymerization

信号调节的核肌动蛋白聚合才刚刚开始出现作为一个主要的细胞过程，然而，其潜在的机制和功能的后果仍然知之甚少。我们最近在完整的哺乳动物细胞中发现了血清刺激的核肌动蛋白网络组装。我们确定了formins mDia 1/2作为负责肌动蛋白成核因子，并证明了核肌动蛋白丝形成和SRF转录活性之间的直接机制联系。然而，核肌动蛋白组装在非常普遍和生理的细胞过程中是否有功能仍不清楚。这是该建议的目的，以研究核肌动蛋白聚合在两个基本的细胞机制：（i）我们目前观察到核肌动蛋白聚合发生在细胞外基质相互作用期间，这似乎是由整联蛋白信号传导和核骨架介导的，（ii）有趣的是，我们正在进行的研究进一步揭示，在有丝分裂末期的细胞分裂过程中，一个引人注目的核肌动蛋白网络以高度明确的方式形成，这表明，在染色质重组中的作用。因此，我们计划定义和解开的分子机制，核肌动蛋白聚合触发的mechanotransduction以及有丝分裂。这些研究将有助于确定新的概念和有前途的药理学药物靶点，以干扰恶性细胞增殖和粘附。

Signal-regulated nuclear actin polymerization is just beginning to emerge as a principal cellular process; however, underlying mechanisms and functional consequences remain poorly understood. We recently discovered serum-stimulated nuclear actin network assembly in intact mammalian cells. We identified the formins mDia1/2 as the responsible actin nucleation factors and demonstrated a direct mechanistic link between nuclear actin filament formation and SRF transcriptional activity. Nevertheless, whether there is a function of nuclear actin assembly during very general and physiological cellular processes remains unclear. It is the aim of this proposal to investigate nuclear actin polymerization in two fundamental cellular mechanisms: (i) we currently observe that nuclear actin polymerization occurs during extracellular matrix interactions, which appear to be mediated by integrin signaling and the nucleoskeleton, (ii) interestingly, our ongoing studies further reveal that a striking nuclear actin network forms in a highly defined manner during cell division at the end of mitosis indicative for a role in chromatin reorganization. We therefore plan to define and unravel the molecular mechanisms underlying nuclear actin polymerization triggered by mechanotransduction as well as by mitosis. These studies shall help in identifying novel concepts and promising pharmacological drug targets to interfere with malignant cell proliferation and adhesion.