title: RUNX1 and its fusion oncoprotein derivative, RUNX1-ETO, induce senescence-like growth arrest independently of replicative stress.
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 fibroblasts and the failure of RAS-induced senescence in Runx2-deficient cells. We now show that RUNX1 induces senescence in human primary fibroblasts. 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 fibroblasts, 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.
authors.affiliation: Molecular Oncology Laboratory, Faculty of Veterinary Medicine, Institute of Comparative Medicine, University of Glasgow, Bearsden, Glasgow, Scotland.
authors.forename: K
authors.initials: K
authors.lastname: Wolyniec
authors.forename: S
authors.initials: S
authors.lastname: Wotton
authors.forename: A
authors.initials: A
authors.lastname: Kilbey
authors.forename: A
authors.initials: A
authors.lastname: Jenkins
authors.forename: A
authors.initials: A
authors.lastname: Terry
authors.forename: G
authors.initials: G
authors.lastname: Peters
authors.forename: C
authors.initials: C
authors.lastname: Stocking
authors.forename: E
authors.initials: E
authors.lastname: Cameron
authors.forename: J C
authors.initials: JC
authors.lastname: Neil
mesh_terms: D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics / Q000502:physiology; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D052816:Foreskin / Q000166:cytology; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D000075142:RUNX1 Translocation Partner 1 Protein; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D019941:Cyclin-Dependent Kinase Inhibitor p16; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; C493728:RUNX1 protein, human; D017382:Reactive Oxygen Species; C488373:TEL-RUNX1 fusion protein, human; D016159:Tumor Suppressor Protein p53; D048051:p38 Mitogen-Activated Protein Kinases; D018631:ras Proteins