R-Ras Proteins and TGF-Beta in Cancer

Abstract

The development of cancer in humans is characterized by the accumulation of genetic alterations that either enhance or diminish activity in signaling pathways mediating cellular growth and proliferation. Over time these alterations gradually transform normal cells into malignant cells with aberrant properties. This process of transformation gives rise to cancerous cells no longer under control by natural growth-regulatory mechanisms within the body. The signaling pathways that govern cell growth and proliferation are mediated in part through the activity of regulatory GTPases, and the R-Ras family of GTPases has been implicated in the promotion of tumorigenesis. Here we investigate the transforming properties of two highly homologous members of the R-Ras family. R-Ras and TC21(R-Ras2) are two Ras-related GTPases with the potential to induce oncogenic transformation in mammalian cells. Despite their similarities, these proteins have distinct functions and differ in their ability to transform cells in vitro and induce tumor formation in vivo. We hypothesized that these differences in tumorigenicity resulted from differential activation of signaling pathways mediating growth and proliferation downstream of R-Ras and TC21. Using mammary epithelial cells we show that TC21 is significantly more transforming than R-Ras, and we demonstrate that distinct signaling events are required for these oncogenes to induce cellular transformation. Transforming growth factor-beta (TGF-â) is a key regulator of cell growth in the body. TGF-â can cooperate with oncogenic members of the Ras superfamily to trigger cell transformation, yet it is unknown whether TGF-â exhibits this type of cooperative behavior with R-Ras and TC21. We investigated this possibility and found R-Ras-transformation to be highly dependent on TGF-â-signaling, while TC21-transformation was less dependent. Through these studies we have generated an in vitro/in vivo model of tumorigenesis that can be used to investigate the molecular events mediating R-Ras and TC21-induced transformation. Importantly, this model will be useful for identifying structural domains that mediate the oncogenic activity of R-Ras proteins, and for testing the efficacy of small molecule inhibitors as potential cancer therapeutics.