Oncogenic Ras Enhances NF-kappaB Transcriptional Activity Through Raf-dependent and Raf-independent Mitogen-activated Protein Kinase Signaling Pathways

Tumors frequently contain mutations in ras genes, resulting in constitutive activation of Ras-activated signaling pathways. The ultimate targets of these signal transduction cascades are transcription factors required for cellular proliferation. Understanding how constitutive activation of Ras contributes to tumorigenesis requires an understanding of both the signaling pathways that Ras activates and how these pathways in turn regulate gene expression. Gene expression from kappaB sites is enhanced in cells transformed with activated Ras and NF-kappaB activity is required for oncogenic Ras to transform NIH-3T3 and Rat-1 fibroblasts. Both dominant negative and constitutively active components of signaling pathways have been tested for their ability to regulate NF-kappaB. These experiments show that Ras utilizes Raf-dependent and Raf-independent pathways to activate NF-kappaB transcriptional activity, both of which require the stress-activated kinase p38 or a related kinase. In the case of Raf, activation of NF-kappaB by an autocrine factor stimulates kappaB-dependent transcriptional activity.