Runx2 disruption promotes immortalization and confers resistance to oncogene-induced senescence in primary murine fibroblasts.
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-Ras(V12)-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-G(2)-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.
Kilbey
Anna
A
Molecular Oncology Laboratory, Institute of Comparative Medicine, Faculty of Veterinary Medicine, University of Glasgow, Glasgow, United Kingdom. A.Kilbey@vet.gla.ac.uk
Blyth
Karen
K
Wotton
Sandy
S
Terry
Anne
A
Jenkins
Alma
A
Bell
Margaret
M
Hanlon
Linda
L
Cameron
Ewan R
ER
Neil
James C
JC
D016475:3T3 Cells; D000818:Animals; D015153:Blotting, Western; D002453:Cell Cycle; D002471:Cell Transformation, Neoplastic; D016922:Cellular Senescence; D003114:Colony-Forming Units Assay; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000502:physiology*; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000502:physiology*; D011905:Genes, ras / Q000502:physiology*; D047468:Immunoprecipitation; D051379:Mice; D008819:Mice, Nude
D050659:Core Binding Factor Alpha 1 Subunit; C493716:Runx2 protein, mouse; D018844:Cyclin-Dependent Kinases