Abstract
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-γ, IL-1β and TNF-α) 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-Racl 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.
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Abbreviations
- NO:
-
nitric oxide
- NOS:
-
nitric oxide synthase
- INF:
-
interferon
- IL:
-
interleukin
- TNF:
-
tumor necrosis factor
- LPS:
-
lypopolysaccharides
- MAPK:
-
mitogen-activated protein kinase.
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Acknowledgements
We would like to thank Dr Channing Der for the wild-type and mutants of Ras, RhoA and Rac1, Dr Richard Jove for dominant negative Erk (Her et al., 1993) and Dr Allan Hall for the RhoB mutants. This work was supported by NCI grant CA67771 (SM Sebti).
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Delarue, F., Taylor, B. & Sebti, S. 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. Oncogene 20, 6531–6537 (2001). https://doi.org/10.1038/sj.onc.1204801
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DOI: https://doi.org/10.1038/sj.onc.1204801
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