Joneson T, Bar-Sagi D
Department of Molecular Genetics and Microbiology, State University of New York at Stony Brook, Stony Brook, New York 11794-5222, USA.
Mol Cell Biol. 1999 Sep;19(9):5892-901. doi: 10.1128/MCB.19.9.5892.
Ras is an essential component of signal transduction pathways that control cell proliferation, differentiation, and survival. In this study we have examined the cellular responses to high-intensity Ras signaling. Expression of increasing amounts of the oncogenic form of human HRas, HRasV12, results in a dose-dependent induction of apoptosis in both primary and immortalized cells. The induction of apoptosis by HRasV12 is blocked by activated Rac and potentiated by dominant interfering Rac. The ability of Rac to suppress Ras-induced apoptosis is dependent on effector pathway(s) controlled by the insert region and is linked to the activation of NF-kappaB. The apoptotic effect of HRasV12 requires the activation of both the ERK and JNK mitogen-activated protein kinase cascade and is independent of p53. These results demonstrate a role for Rac in controlling signals that are necessary for cell survival, and suggest a mechanism by which Rac activity can confer growth advantage to cells transformed by the ras oncogene.
Ras是控制细胞增殖、分化和存活的信号转导通路的重要组成部分。在本研究中，我们检测了细胞对高强度Ras信号的反应。人HRas致癌形式HRasV12表达量的增加，会导致原代细胞和永生化细胞中凋亡的剂量依赖性诱导。活化的Rac可阻断HRasV12诱导的凋亡，而显性干扰Rac则可增强这种凋亡。Rac抑制Ras诱导凋亡的能力取决于由插入区域控制的效应器途径，并与NF-κB的激活有关。HRasV12的凋亡作用需要ERK和JNK丝裂原活化蛋白激酶级联的激活，且与p53无关。这些结果证明了Rac在控制细胞存活所需信号中的作用，并提示了一种机制，通过该机制Rac活性可赋予由ras癌基因转化的细胞生长优势。
