Back to Search
Start Over
Runx2 deficiency and defective subnuclear targeting bypass senescence to promote immortalization and tumorigenic potential
- Source :
- Proceedings of the National Academy of Sciences of the United States. Dec 11, 2007, Vol. 104 Issue 50, p19861, 6 p.
- Publication Year :
- 2007
-
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 [beta]-gal activity and p[16.sup.INK4]a tumor suppressor expression. Primary Runx2-null osteoblasts have a growth advantage and exhibit loss of p[21.sup.wAF1/CIP1] and p[19.sup.ARF] expression. Reintroduction of WT Runx2, but not a subnuclear targeting-defective mutant, induces both p[21.sup.WAF/CIP1] and p[19.sup.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. cancer | genomic instability | growth control | nuclear organization | osteoblast
Details
- Language :
- English
- ISSN :
- 00278424
- Volume :
- 104
- Issue :
- 50
- Database :
- Gale General OneFile
- Journal :
- Proceedings of the National Academy of Sciences of the United States
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.172906899