Esteve P, Embade N, Perona R, Jiménez B, del Peso L, León J, Arends M, Miki T, Lacal J C
Instituto de Investigaciones Biomédicas, CSIC and Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma, Madrid, Spain.
Oncogene. 1998 Oct 8;17(14):1855-69. doi: 10.1038/sj.onc.1202082.
Rho proteins are a branch of GTPases that belongs to the Ras superfamily which are critical elements of signal transduction pathways leading to a variety of cellular responses. This family of small GTPases has been involved in diverse biological functions such as cytoskeleton organization, cell growth and transformation, cell motility, migration, metastasis, and responses to stress. We report that several human Rho proteins including Rho A, Rho C and Rac 1, are capable of inducing apoptosis in different cell systems like murine NIH3T3 fibroblasts and the human erythroleukemia K562 cell line. Since K562 cells are devoid of p53, apoptosis induced by Rho in this system is independent of p53. Rho-dependent apoptosis is mediated by the generation of ceramides, and it is drastically inhibited by ectopic expression of Bcl2, both under in vitro and in vivo conditions. Furthermore, the human oncogenes vav and ost that have been shown to function as guanine exchange factors for Rho proteins, were also able to induce apoptosis under similar conditions. Finally, we also report that the levels of endogenous Rho proteins are increased when U937 myeloid leukemia cells are exposed to apoptosis-inducing conditions such as TNF alpha treatment. Furthermore, TNF alpha-induced apoptosis in these cells is inhibited by expression of a dominant negative mutant of Rac 1 but it is not affected by a similar mutant of Rho A. These results suggest that Rho proteins play an important role in the physiological regulation of the apoptotic response to stress-inducing agents.
Rho蛋白是属于Ras超家族的GTP酶的一个分支，是导致多种细胞反应的信号转导途径的关键要素。这个小GTP酶家族参与了多种生物学功能，如细胞骨架组织、细胞生长与转化、细胞运动、迁移、转移以及应激反应。我们报道，包括Rho A、Rho C和Rac 1在内的几种人类Rho蛋白，能够在不同的细胞系统中诱导凋亡，如小鼠NIH3T3成纤维细胞和人类红白血病K562细胞系。由于K562细胞缺乏p53，在这个系统中由Rho诱导的凋亡不依赖于p53。Rho依赖性凋亡是由神经酰胺的生成介导的，并且在体外和体内条件下，均被Bcl2的异位表达显著抑制。此外，已被证明作为Rho蛋白的鸟嘌呤交换因子发挥作用的人类癌基因vav和ost，在类似条件下也能够诱导凋亡。最后，我们还报道，当U937髓系白血病细胞暴露于凋亡诱导条件（如TNFα处理）时，内源性Rho蛋白的水平会升高。此外，这些细胞中TNFα诱导的凋亡被Rac 1显性负突变体的表达所抑制，但不受Rho A类似突变体的影响。这些结果表明，Rho蛋白在对应激诱导剂的凋亡反应的生理调节中起重要作用。
