ABSTRACT
Given the prevalence of Ras mutations in human cancer, it is critical to understand the effector pathways downstream of oncogenic Ras leading to transformation. To directly assess the requirement for Rac1 in K-ras-induced tumorigenesis, we employed a model of lung cancer in which an oncogenic allele of K-ras could be activated by Cre-mediated recombination in the presence or absence of conditional deletion of Rac1. We show that Rac1 function is required for tumorigenesis in this model. Furthermore, although Rac1 deletion alone was compatible with cell viability and proliferation, when combined with K-ras activation in primary epithelial cells, loss of Rac1 caused a profound reduction in proliferation. These data show a specific requirement for Rac1 function in cells expressing oncogenic K-ras.
Subject(s)
Adenocarcinoma/genetics , Adenoma/genetics , Cell Transformation, Neoplastic/genetics , Genes, ras/physiology , Lung Neoplasms/genetics , Neuropeptides/physiology , rac GTP-Binding Proteins/physiology , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Adenoma/mortality , Adenoma/pathology , Animals , Cells, Cultured , Disease Progression , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Mice , Mice, Transgenic , rac1 GTP-Binding ProteinABSTRACT
The Rac1 guanosine triphosphatase (GTPase) has been implicated in multiple cellular functions, including actin dynamics, proliferation, apoptosis, adhesion, and migration resulting from signaling by multiple receptors, including the B cell antigen receptor (BCR). We used conditional gene targeting to generate mice with specific Rac1 deficiency in the B cell lineage. In the absence of both Rac1 and the highly related Rac2, B cell development was almost completely blocked. Both GTPases were required to transduce BCR signals leading to proliferation, survival and up-regulation of BAFF-R, a receptor for BAFF, a key survival molecule required for B cell development and maintenance.
