Integrative nuclear modulation of the Hedgehog transcriptional profile (.2)

在许多生理过程中，响应不断变化的环境条件并将这些变化落实到细胞基因表达谱中是非常重要的。然而，在物理信号的情况下，如底物硬度的变化，通常并不完全清楚这些信息是如何通过分子传递到关键信号节点以影响细胞转录组的。在这里，我们想重点介绍Hedgehog(HH)/GLI途径，这是发育和癌症中的一个重要信号系统。我们以前的工作暗示了新的蛋白质复合体(肌动蛋白-MAL-GLI1和KDM-GLI1)能够作为分子平台收集细胞信息并将这些数据传递给GLI1转录因子。具体地说，我们将研究外部信号，如底物硬度或细胞内在信息，如细胞形状或代谢，如何影响HH途径和HH驱动的生理过程，如细胞分化。此外，还将对我们之前确认的两种蛋白质复合体进行详细的生化分析。我们认为，蛋白质复合体的这种整合功能不仅在生理环境中对非规范途径的激活具有重要意义，而且在癌症或纤维化等病理情况下也具有重要意义。因此，了解这些信号复合体的生物学对于未来的治疗干预至关重要。

Responding to changing environmental conditions and implementing these changes into the cellular gene expression profile is highly important during many physiological processes. However, in the case of physical cues such as a changing substrate stiffness it is most often not entirely clear how such information is molecularly relayed to critical signaling nodes in order to impact on the cellular transcriptome. Here, we would like to focus on the Hedgehog (Hh)/GLI pathway, an essential signaling system in development and cancer. Our previous work hints to novel protein complexes (Actin-MAL-GLI1 and KDM-GLI1) capable of serving as molecular platforms gathering cellular information and conveying these data to the GLI1 transcription factor. Specifically, we will investigate how external cues such as substrate stiffness or cell-intrinsic information such as cell shape or metabolism impact on the Hh pathway and on Hh-driven physiological processes such as cell differentiation. This will be complemented by a detailed biochemical analysis of the two protein complexes previously identified by us. We believe that such integrative functions of protein complexes are of high significance for non-canonical pathway activation in physiological settings but also in pathological situations such as cancer or fibrosis. Hence, understanding the biology of these signaling complexes is crucial for future therapeutic interventions.