Rho-regulated signals induce apoptosis in vitro and in vivo by a p53-independent, but Bcl2 dependent pathway
Rho-regulated signals induce apoptosis in vitro and in vivo by a p53-independent, but Bcl2 dependent pathway
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DOI：
10.1038/sj.onc.1202082
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发表时间：
1998-10-08
期刊：
影响因子：
8
通讯作者：
Lacal, JC
中科院分区：
文献类型：
--
作者：
Esteve, P;Embade, N;Lacal, JC
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通路的关键元件。这个小的GTP酶家族参与了多种生物学功能，如细胞骨架组织、细胞生长和转化、细胞运动、迁移、转移和应激反应。我们报道了几种人Rho蛋白，包括Rho A、Rho C和Rac I，能够诱导不同的细胞系统，如小鼠NIH3T3成纤维细胞和人红白血病K562细胞系。由于K562细胞缺乏P53，Rho在这个系统中诱导的凋亡不依赖于P53，Rho依赖的凋亡是由神经酰胺的产生介导的，在体外和体内条件下，Bcl2的异位表达都强烈地抑制了Rho依赖的凋亡。此外，人类癌基因Vav和ost已被证明是Rho蛋白的鸟嘌呤交换因子，在类似的条件下也能够诱导细胞凋亡。最后，我们还报道了当U937髓系白血病细胞暴露在诱导凋亡的条件下，如肿瘤坏死因子α治疗时，内源性Rho蛋白水平增加。此外，肿瘤坏死因子α诱导的细胞凋亡可被Rac 1的显性负性突变体抑制，但不受Rho A类似突变体的影响。这些结果表明，Rho蛋白在应激诱导的细胞凋亡反应中起着重要的生理调节作用。
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 I, 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.