Oncogene-induced senescence: an essential role for Runx

Kilbey, A., Terry, A., Cameron, E.R. and Neil, J.C. (2008) Oncogene-induced senescence: an essential role for Runx. Cell Cycle, 7(15), pp. 2333-2340.

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Oncogene induced senescence (OIS) was first observed following expression of an oncogenic form of RAS in normal human fibroblasts.1 This process resembles replicative senescence, a phenomenon observed in aged cultures of primary human fibroblasts which is generally attributed to telomere attrition and resultant loss of proliferative capacity.2 While the in vivo relevance of OIS was at first questioned, its significance was strongly supported by a dependence on tumour suppressor networks that impinge on the p53 and pRb pathways.1,3-6 More recently, the demonstration that certain oncogenes can elicit a senescence response in vivo provided unambiguous evidence that OIS is an important mode of tumour suppression.7-9 Moreover, while most mechanistic studies of OIS have been conducted in fibroblasts in vitro, it is important to note that a similar phenomenon can be observed in a range of cell lineages in vivo.7-11While its importance is now beyond doubt, there are many key questions that remain unanswered with regard to OIS. How homogeneous is this response in different cellular contexts and which aspects of the phenotype are of fundamental importance? Activated oncogenes such as H-RasV12 arrest cell cycle progression beyond the quiescence restriction point in G1 or G2 with no concomitant block in cell growth.12 A hypertrophic senescent condition ensues characterised by a flat and enlarged morphology, an increase in acidic β-galactosidase activity and dramatic chromatin condensations affecting proliferation promoting genes such as cyclin A.13,14 Recent studies suggest that a definition of OIS on the basis of phenotypic traits of human primary fibroblasts undergoing Ras-induced senescence may be too restrictive and that there are differences between human and mouse fibroblasts as well as between fibroblasts from different tissues sources, and indeed other cell types.15 Another key question is whether the process is invariably an aberrant response to mitogenic signalling and if so how important is DNA damage signalling and chromatin remodelling for execution of the phenotyope? And finally, which factors define the relative stability of OIS in different cell backgrounds? Is it the strength of the signal, its duration or the cellular context in which it is expressed that is the key?To shed light on these questions, we begin with a review of the essential players and pathways in OIS, focusing mainly on evidence gleaned from murine systems where genetic ablation and inhibitor studies have been combined to increase our understanding. The requirement for specific pathways and players will be reviewed particularly in the context of Ras-induced senescence. We will then consider evidence for the Runx gene family that have recently emerged as important mediators of OIS. Finally we will attempt to build these observations into a coherent picture and suggest fruitful ways ahead to understand and exploit this knowledge in the control of cancer cell behaviour.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Cameron, Professor Ewan and Neil, Professor James and Kilbey, Dr Anna and Terry, Mrs Anne
Authors: Kilbey, A., Terry, A., Cameron, E.R., and Neil, J.C.
College/School:College of Medical Veterinary and Life Sciences > School of Veterinary Medicine
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Cell Cycle

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