Dingal P C Dave P, Discher Dennis E
Molecular and Cell Biophysics Laboratory, Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, Pennsylvania.
Molecular and Cell Biophysics Laboratory, Department of Chemical and Biomolecular Engineering, University of Pennsylvania, Philadelphia, Pennsylvania; Graduate Groups in Physics and Cell & Molecular Biology, University of Pennsylvania, Philadelphia, Pennsylvania.
Biophys J. 2014 Dec 2;107(11):2734-43. doi: 10.1016/j.bpj.2014.10.042.
Mechanotransduction pathways convert forces that stress and strain structures within cells into gene expression levels that impact development, homeostasis, and disease. The levels of some key structural proteins in the nucleus, cytoskeleton, or extracellular matrix have been recently reported to scale with tissue- and cell-level forces or mechanical properties such as stiffness, and so the mathematics of mechanotransduction becomes important to understand. Here, we show that if a given structural protein positively regulates its own gene expression, then stresses need only inhibit degradation of that protein to achieve stable, mechanosensitive gene expression. This basic use-it-or-lose-it module is illustrated by application to meshworks of nuclear lamin A, minifilaments of myosin II, and extracellular matrix collagen fibers—all of which possess filamentous coiled-coil/supercoiled structures. Past experiments not only suggest that tension suppresses protein degradation mediated and/or initiated by various enzymes but also that transcript levels vary with protein levels because key transcription factors are regulated by these structural proteins. Coupling between modules occurs within single cells and between cells in tissue, as illustrated during embryonic heart development where cardiac fibroblasts make collagen that cardiomyocytes contract. With few additional assumptions, the basic module has sufficient physics to control key structural genes in both development and disease.
机械转导通路将作用于细胞内结构的应力和应变力转化为影响发育、体内平衡和疾病的基因表达水平。最近有报道称，细胞核、细胞骨架或细胞外基质中一些关键结构蛋白的水平与组织和细胞水平的力或机械特性（如硬度）成比例，因此理解机械转导的数学原理变得很重要。在这里，我们表明，如果一种给定的结构蛋白正向调节其自身的基因表达，那么应力只需抑制该蛋白的降解就能实现稳定的、机械敏感的基因表达。这种基本的“用进废退”模块通过应用于核纤层蛋白A网络、肌球蛋白II微丝和细胞外基质胶原纤维得到了说明——所有这些都具有丝状卷曲螺旋/超螺旋结构。过去的实验不仅表明张力会抑制各种酶介导和/或引发的蛋白质降解，还表明转录水平会随蛋白质水平而变化，因为关键转录因子受这些结构蛋白的调控。模块之间的耦合发生在单个细胞内和组织中的细胞之间，如在胚胎心脏发育过程中，心脏成纤维细胞产生心肌细胞收缩的胶原蛋白。只需很少的额外假设，这个基本模块就有足够的物理学原理来控制发育和疾病中的关键结构基因。
