Abstract
The osteogenic Runt-related (Runx2) transcription factor negatively regulates proliferation and ribosomal gene expression in normal diploid osteoblasts, but is up-regulated in metastatic breast and prostate cancer cells. Thus, Runx2 may function as a tumor suppressor or an oncogene depending on the cellular context. Here we show that Runx2-deficient primary osteoblasts fail to undergo senescence as indicated by the absence of β-gal activity and p16INK4a tumor suppressor expression. Primary Runx2-null osteoblasts have a growth advantage and exhibit loss of p21WAF1/CIP1 and p19 ARF expression. Reintroduction of WT Runx2, but not a subnuclear targeting-defective mutant, induces both p21WAF/CIP1 and p19 ARF mRNA and protein resulting in cell-cycle inhibition. Accumulation of spontaneous phospho-H2A.X foci, loss of telomere integrity and the Mre11/Rad50/Nbs1 DNA repair complex, and a delayed DNA repair response all indicate that Runx2 deficiency leads to genomic instability. We propose that Runx2 functions as a tumor suppressor in primary diploid osteoblasts and that subnuclear targeting contributes to Runx2-mediated tumor suppression.
Original language | English (US) |
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Pages (from-to) | 19861-19866 |
Number of pages | 6 |
Journal | Proceedings of the National Academy of Sciences of the United States of America |
Volume | 104 |
Issue number | 50 |
DOIs | |
State | Published - Dec 11 2007 |
Keywords
- Cancer
- Genomic instability
- Growth control
- Nuclear organization
- Osteoblast
ASJC Scopus subject areas
- General