The Functions of Ras

Ras has been described to promote proliferation, suppress apoptosis, alter cell metabolism, disrupt morphogenesis, promote evasion of the immune system, induce remodeling of the microenvironment and stimulate metastasis. These functions are described below.

Promotion of proliferation
In normal cycling cells, Ras transmits mitogenic stimuli required for progression through G1. In tumor cells, mutant Ras hijacks the same pathways to promote hyperproliferation. For instance, active Ras increases the transcription of growth factors that provide the stimulus for proliferation as well as the expression of the growth factor receptors themselves. In addition, active Ras upregulates transcription factors involved in the expression of cyclin D1. Furthermore, phosphorylation of GSK3β by AKT downstream of PI3K and Ras suppresses the ability of GSK3β to phosphorylate cyclin D1 and promote its degradation. The critical nature of cyclin D1 regulation by Ras was tested in mouse models, which revealed that, at least in some cases, Ras-driven tumors were dependent on cyclin D1. Ras is also known to suppress cell cycle inhibitors such as p21 and p27. Finally, Ras is known to stabilize c-myc, a master transcription regulator that promotes proliferation, through phosphorylation by ERK and prevent c-myc degradation by inhibiting GSK3β, through PI3K.

Suppression of apoptosis
Apoptosis, also known as programmed cell death, can be triggered by internal signaling from the mitochondria or external signaling through death receptors that converge in the activation of caspase-3. These cellular pathways comprise a major defense mechanism against tumor maintenance and progression. Interestingly, mouse
models of mutant Ras-driven melanoma and lung cancer have shown that withdrawal of oncogenic Ras signaling leads to widespread apoptosis. Oncogenic Ras can suppress apoptosis by a number of mechanisms.
Downstream of PI3K, Ras activation leads to downregulation of BCL-2-homologous antagonist/killer 1 (BAK1) levels, a pro-apoptotic protein that promotes mitochondrial-dependent apoptosis, and increases the levels of inhibitors of apoptosis (IAPs). Ras activation also leads to Raf-dependent downregulation of the pro-apoptotic transcriptional repressor prostate apoptosis response 4 (PAR4) as well as upregulation of the anti-apoptotic BCL-2 and apoptosis regulator with caspase recruitment domain (ARC). Both PI3K and Raf pathways lead to phosphorylation of BAD, which prevents its pro-apoptotic functions. Incontrast, Ras has been shown to have proapoptotic functions through Raf-mediated induction of p53 in addition to RASSF1, NORE1, MST1 and JNK mediated regulation of caspase-3, BAK1 and Bcl-2 associated X protein (BAX). However, these pro-apoptotic functions are hypothesized to be more important in normal cells.

Alterations in metabolism
Many cancer cells shift their primary metabolic pathway from oxidative phosphorylation to anaerobic glycolysis, a change known as the Warburg effect. It is theorized that the Warburg effect occurs because anaerobic glycolysis better provides macromolecules needed as precursors for cell growth. Interestingly, the same oncogenic pathways that regulate proliferation also regulate metabolic pathways. For instance, c-myc overexpression promotes both proliferation and glutamine addiction while PI3K regulates glucose metabolism. A primary role of oncogenic Ras is to upregulate expression of hypoxiainducible factor la (HIFla), which binds to constitutively expressed HIFip to form the HIF transcription factor. In normal cells, HIF signaling results from sensing low oxygen levels and logically leads to a shift to anaerobic glycolysis. In Ras mutant cells, PI3K activates AKT, which activates mTOR-mediated translation of HIFla. Ras also increases transcription of the glucose transporter GLUT1, increasing the availability of glucose in the cell. Furthermore, Ras increases the levels of key enzymes in glycolysis, including hexokinase and phosphofructokinase. A more recently discovered contribution of Ras to metabolism is an upregulation of autophagy.