RUNX1 and its fusion oncoprotein derivative, RUNX1-ETO, induce senescence-like growth arrest independently of replicative stress

Wolyniec, K., Wotton, S., Kilbey, A., Jenkins, A., Terry, A., Peters, G., Stocking, C., Cameron, E.R. and Neil, J.C. (2009) RUNX1 and its fusion oncoprotein derivative, RUNX1-ETO, induce senescence-like growth arrest independently of replicative stress. Oncogene, 28(27), pp. 2502-2512. (doi: 10.1038/onc.2009.101)

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Abstract

A role for the RUNX genes in cancer fail-safe processes has been suggested by their induction of senescence-like growth arrest in primary murine. broblasts and the failure of RAS-induced senescence in Runx2-deficient cells. We now show that RUNX1 induces senescence in human primary. broblasts. High-affinity DNA binding is necessary but not sufficient, as shown by the functional attenuation of the truncated RUNX1/AML1a isoform and the TEL-RUNX1 fusion oncoprotein. However, a similar phenotype was potently induced by the RUNX1-ETO (AML1-ETO) oncoprotein, despite its dominant-negative potential. A detailed comparison of H-RAS(V12), RUNX1 and RUNX1-ETO senescent phenotypes showed that the RUNX effectors induce earlier growth stasis with only low levels of DNA damage signaling and a lack of chromatin condensation, a marker of irreversible growth arrest. In human. broblasts, all effectors induced p53 in the absence of detectable p14(Arf), whereas only RUNX1-ETO induced senescence in p16(Ink4a)-null cells. Correlation was noted between induction of p53, reactive oxygen species and phospho-p38, whereas p38(MAPK) inhibition rescued cell growth markedly. These findings indicate a role for replication-independent pathways in RUNX and RUNX1-ETO senescence, and show that the context-specific oncogenic activity of RUNX1 fusion proteins is mirrored in their distinctive interactions with fail-safe responses.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Cameron, Professor Ewan and Neil, Professor James and Mcdonald, Mrs Alma and Kilbey, Dr Anna and Terry, Mrs Anne
Authors: Wolyniec, K., Wotton, S., Kilbey, A., Jenkins, A., Terry, A., Peters, G., Stocking, C., 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:Oncogene
Publisher:Nature Publishing Group
ISSN:0950-9232
ISSN (Online):1476-5594
Published Online:18 May 2009

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