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 |
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Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Cameron, Professor Ewan and Kilbey, Dr Anna and Neil, Professor James and Mcdonald, Mrs Alma 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 Biodiversity, One Health & Veterinary Medicine College of Medical Veterinary and Life Sciences > School of Infection & Immunity College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research |
Journal Name: | Oncogene |
Publisher: | Nature Publishing Group |
ISSN: | 0950-9232 |
ISSN (Online): | 1476-5594 |
Published Online: | 18 May 2009 |
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