Moustakas A, Stournaras C
Department of Biochemistry, Division of Basic Sciences, School of Medicine, University of Crete, Heraklion, Greece.
J Cell Sci. 1999 Apr;112 ( Pt 8):1169-79. doi: 10.1242/jcs.112.8.1169.
The actin cytoskeleton undergoes architectural changes during the processes of cell transformation and tumourigenesis. Transforming growth factors beta arrest cell cycle progression, regulate differentiation and modulate the onset of oncogenesis and tumourigenesis. Here, we investigated the direct role of transforming growth factor beta-1 in altering the transformed phenotype and regulating the actin organisation of oncogenic fibroblasts that constitutively or inducibly express the H-ras oncogene. Following transforming growth factor beta-1 treatment, these transformed fibroblasts undergo a dramatic morphological alteration that includes a discrete reorganisation of their actin cytoskeleton and focal adhesions. Quantitative biochemical analysis demonstrated that transforming growth factor beta-1 potently induced polymerisation of globular to filamentous actin, thus corroborating the morphological analysis. The effect of transforming growth factor beta-1 on the cytoskeleton correlates with the ability of this cytokine to suppress anchorage-independent growth of the transformed fibroblasts. Furthermore, transforming growth factor beta-1 upregulates considerably the levels of the RhoB small GTPase and less the RhoA levels. Finally, The beta GTPase inhibitor, C3 exotransferase, blocks the ability of TGF-beta1 to induce cytoskeletal reorganisation. These findings indicate that transforming growth factor beta can regulate cell morphology and growth in a concerted manner possibly via mechanisms that control the actin cytoskeleton.
在细胞转化和肿瘤发生过程中，肌动蛋白细胞骨架会发生结构变化。转化生长因子β可阻止细胞周期进程、调节分化并调控肿瘤发生和致癌作用的起始。在此，我们研究了转化生长因子β-1在改变转化表型以及调节组成型或诱导型表达H-ras癌基因的致癌成纤维细胞的肌动蛋白组织方面的直接作用。用转化生长因子β-1处理后，这些转化的成纤维细胞会发生显著的形态改变，包括其肌动蛋白细胞骨架和粘着斑的离散重组。定量生化分析表明，转化生长因子β-1能有效诱导球状肌动蛋白聚合成丝状肌动蛋白，从而证实了形态学分析结果。转化生长因子β-1对细胞骨架的作用与其抑制转化成纤维细胞非锚定依赖性生长的能力相关。此外，转化生长因子β-1能显著上调RhoB小GTP酶的水平，而对RhoA水平的上调作用较小。最后，βGTP酶抑制剂C3外切转移酶可阻断TGF-β1诱导细胞骨架重组的能力。这些发现表明，转化生长因子β可能通过控制肌动蛋白细胞骨架的机制以协同方式调节细胞形态和生长。
