Runx2 deficiency and defective subnuclear targeting bypass senescence to promote immortalization and tumorigenic potential

doi:10.1073/pnas.0709650104

Runx2 deficiency and defective subnuclear targeting bypass senescence to promote immortalization and tumorigenic potential

Department of Cell Biology and Cancer Center, University of Massachusetts Medical School and Cancer Center, 55 Lake Avenue North, Worcester, MA 01655

Communicated by Sheldon Penman, Massachusetts Institute of Technology, Cambridge, MA, October 11, 2007 (received for review September 20, 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 β-gal activity and p16^INK4a tumor suppressor expression. Primary Runx2-null osteoblasts have a growth advantage and exhibit loss of p21^WAF1/CIP1 and p19^ARF expression. Reintroduction of WT Runx2, but not a subnuclear targeting-defective mutant, induces both p21^WAF/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.

Footnotes

*To whom correspondence should be addressed. E-mail: gary.stein{at}umassmed.edu
Author contributions: S.K.Z., J.L.S., J.B.L., A.J.v.W., and G.S.S. designed research; S.K.Z., S.P., J.P., T.G., S.G., and S.A.A. performed research; S.K.Z., S.P., J.P., T.G., S.G., S.A.A., J.L.S., J.B.L., A.J.v.W., and G.S.S. analyzed data; and S.K.Z., J.L.S., J.B.L., A.J.v.W., and G.S.S. wrote the paper.
The authors declare no conflict of interest.