Ras and RhoA suppress whereas RhoB enhances cytokine-induced transcription of nitric oxide synthase-2 in human normal liver AKN-1 cells and lung cancer A-549 cells

被引:27
作者
Delarue, FL
Taylor, BS
Sebti, SM
机构
[1] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Drug Discovery Program, Tampa, FL 33612 USA
[2] Univ S Florida, Dept Oncol, Tampa, FL USA
[3] Univ Pittsburgh, Sch Med, Dept Surg, Pittsburgh, PA USA
关键词
NOS-2; Ras; RhoA; RhoB; Erk; cytokines;
D O I
10.1038/sj.onc.1204801
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
While both nitric oxide synthase-2 (NOS-2) and low molecular weight GTPases, such as Ras and Rho, have been implicated in malignant transformation, the cross talk between these important proteins is ill understood. In this study we examined the ability of H-Ras, RhoA, RhoB and Rac1 to modulate cytokine-induced NOS2. In the normal human liver AKN-1 cell line and in the human non-small cell lung carcinoma cell line, A-549, the ability of the cytokines (INF-gamma, IL-1 beta and TNF-alpha) to activate NOS-2 was blocked by activated L61-H-Ras whereas dominant negative N17-H-Ras enhanced NOS-2 activation. Consistent with this dominant negative Erk2 as well as a MEK inhibitor also enhanced cytokine activation of NOS-2. Furthermore, activated L63-RhoA blocked whereas activated V14-RhoB enhanced cytokine NOS-2 activation. Activated I115-Rac1 did not affect NOS-2 activation. These results demonstrate that the Ras/Erk and the Ras/RhoA pathways negatively regulate whereas RhoB enhances cytokine-induced NOS-2. This is the first demonstration that genes that promote malignant transformation such as Ras and RhoA inhibit, whereas genes with tumor suppresser activity such as RhoB enhance NOS2 induction.
引用
收藏
页码:6531 / 6537
页数:7
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