Regulation and function of nuclear actin polymerization

信号调控的核肌动蛋白聚合才刚刚开始成为一种主要的细胞过程；然而，潜在的机制和功能后果仍然知之甚少。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。我们发现mDia1/2是肌动蛋白的成核因子，并证明了核肌动蛋白细丝的形成和SRF转录活性之间存在直接的机制联系。然而，在非常普遍和生理的细胞过程中，是否存在核肌动蛋白组装的功能仍不清楚。这项建议的目的是从两个基本的细胞机制来研究核肌动蛋白聚合：(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中，这似乎是由整合素信号和核骨架介导的；(Ii)有趣的是，我们正在进行的研究进一步揭示，在有丝分裂结束时，一个显著的核肌动蛋白网络以一种高度明确的方式形成，这表明它在染色质重组中发挥了作用。因此，我们计划定义和解开由机械转导和有丝分裂引发的核肌动蛋白聚合的分子机制。这些研究将有助于确定新的概念和有前景的药物靶点，以干扰恶性细胞的增殖和黏附。

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.