Runx2 disruption promotes immortalization and confers resistance to oncogene-induced senescence in primary murine fibroblasts

Kilbey, A., Blyth, K. , Wotton, S., Terry, A., Jenkins, A., Bell, M., Hanlon, L., Cameron, E.R. and Neil, J.C. (2007) Runx2 disruption promotes immortalization and confers resistance to oncogene-induced senescence in primary murine fibroblasts. Cancer Research, 67(23), pp. 11263-11271. (doi: 10.1158/0008-5472.CAN-07-3016)

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Publisher's URL: http://dx.doi.org/10.1158/0008-5472.CAN-07-3016

Abstract

The Runx genes play paradoxical roles in cancer where they can function either as dominant oncogenes or tumor suppressors according to context. We now show that the ability to induce premature senescence in primary murine embryonic fibroblasts (MEF) is a common feature of all three Runx genes. However, ectopic Runx–induced senescence contrasts with Ras oncogene–induced senescence, as it occurs directly and lacks the hallmarks of proliferative stress. Moreover, a fundamental role for Runx function in the senescence program is indicated by the effects of Runx2 disruption, which renders MEFs prone to spontaneous immortalization and confers an early growth advantage that is resistant to stress-induced growth arrest. Runx2−/− cells are refractory to H-RasV12–induced premature senescence, despite the activation of a cascade of growth inhibitors and senescence markers, and are permissive for oncogenic transformation. The aberrant behavior of Runx2−/− cells is associated with signaling defects and elevated expression of S-G2-M cyclins and their associated cyclin dependent kinase activities that may override the effects of growth inhibitory signals. Coupling of stress responses to the cell cycle represents a novel facet of Runx tumor suppressor function and provides a rationale for the lineage-specific effects of loss of Runx function in cancer. [Cancer Res 2007;67(23):11263–71]

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Blyth, Professor Karen and Cameron, Professor Ewan and Neil, Professor James and Bell, Mrs Margaret and Kilbey, Dr Anna and Jenkins, Mr Andrew and Terry, Mrs Anne
Authors: Kilbey, A., Blyth, K., Wotton, S., Terry, A., Jenkins, A., Bell, M., Hanlon, L., Cameron, E.R., and Neil, J.C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
College of Medical Veterinary and Life Sciences > School of Veterinary Medicine
Journal Name:Cancer Research
ISSN:0008-5472

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