Ras-induced senescence and its physiological relevance in cancer

Abstract

Activated oncogenes like Ras have traditionally been thought as promoting unrestrained proliferation; therefore, the concept of oncogene-induced senescence has been, and still is, controversial. The counter-intuitive notion that activation of oncogenes leads to the prevention of cellular proliferation has initially been fueled by in vitro studies using ectopic expression of activated Ras in primary fibroblasts. While these initial studies demonstrated unambiguously the existence of a new type of cellular senescence, induced by oncogenes in an ex-vivo system, questions were raised about the physiological relevance of this process. Indeed, recent technical advances in mouse modeling for cancer have suggested that the occurrence of Ras-induced senescence is highly dependent on the cellular context, as well as the level of expression of activated Ras, and may not be pertinent to the study of human cancer initiation and/or progression. However, our increased knowledge of the molecular basis for cellular senescence has led to a better understanding of the molecular events modulating cancer progression in vivo. Recent studies have not only clearly established the incidence of cellular senescence in pre-neoplasic lesions, but also its role as a potential tumor-suppressor mechanism in vivo. Here, we review the recent and exciting new findings regarding the physiological relevance of Ras-induced senescence, and discuss their implications in terms of cancer therapy.

Figure 1. Schematic representation of the pathways involved in Ras-induced senescence and their potential crosstalks in the mouse

Oncogene Induced Senescence (OIS) can initially be driven an activating mutation in Ras oncogene and eventual amplification of activated Ras signal. Mutated Ras then induces OIS through the cooperation of the MapK signaling cascade, the DNA damage response pathway and the SASP response. Activation of the MapK cascade leads to p38 activation through a series of phosphorylation events, which then activates MapKap Kinase 3 (3pK), which in turn phosphorylates Bmi1. This phosphorylation, along with chromatin modifications within the Ink4a locus, releases Bmi11 from the Ink4a locus allowing transcription of p16^Ink4a and p19^Arf. Upregulation of p16^Ink4a proteins leads to SAHF formation and therefore repression of E2F target genes. Additionally, amplification of the activated Ras signal leads to the generation of Reactive Oxygen Species (ROS) and replication stress thereby engaging the DNA Damage Response. This response may promote senescence directly though up-regulation p53 in a direct manner, or through the activation of the SASP response. In addition, the DNA Damage Response also contributes to senescence through p53. For details and references, see corresponding section in the text.