Oncogenic Ras enhances NF-kappaB transcriptional activity through Raf-dependent and Raf-independent mitogen-activated...

Area of Science:

• Oncology
• Molecular Biology
• Cell Signaling

Background:

• Ras gene mutations are common in tumors, leading to persistently active Ras signaling pathways.
• These pathways target transcription factors crucial for cell proliferation, contributing to tumorigenesis.
• Understanding Ras-driven tumorigenesis necessitates knowledge of its signaling pathways and their impact on gene expression.

Purpose of the Study:

• To investigate how activated Ras signaling influences gene expression, specifically focusing on NF-kappaB activity.
• To elucidate the specific signaling pathways (Raf-dependent and independent) utilized by Ras to activate NF-kappaB.
• To determine the role of stress-activated kinases, like p38, in Ras-mediated NF-kappaB activation.

Main Methods:

• Utilized dominant-negative and constitutively active signaling pathway components.
• Assessed the regulation of NF-kappaB activity in Ras-transformed cells (NIH-3T3 and Rat-1 fibroblasts).
• Investigated the requirement of p38 kinase or related kinases in Ras-induced NF-kappaB activation.

Main Results:

• Activated Ras enhances gene expression from kappaB sites.
• NF-kappaB activity is essential for oncogenic Ras to transform fibroblasts.
• Ras activates NF-kappaB through both Raf-dependent and Raf-independent pathways.
• Both pathways require the stress-activated kinase p38 or a similar kinase.
• Autocrine factor-mediated activation of NF-kappaB stimulates kappaB-dependent transcription in the context of Raf signaling.

Conclusions:

• Constitutively active Ras signaling contributes to tumorigenesis by activating NF-kappaB transcriptional activity.
• Ras employs distinct Raf-dependent and Raf-independent signaling routes to activate NF-kappaB.
• The stress-activated kinase p38 is a critical mediator in Ras-induced NF-kappaB activation, impacting cell transformation.