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

Sayyed K. Zaidi, Sandhya Pande, Jitesh Pratap, Tripti Gaur, Simina Grigoriu, Syed A. Ali, Janet L. Stein, Jane B. Lian, Andre J. Van Wijnen, Gary S. Stein

Research output: Contribution to journalArticle

61 Scopus citations

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 languageEnglish (US)
Pages (from-to)19861-19866
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number50
DOIs
StatePublished - Dec 11 2007

Keywords

  • Cancer
  • Genomic instability
  • Growth control
  • Nuclear organization
  • Osteoblast

ASJC Scopus subject areas

  • General

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    Zaidi, S. K., Pande, S., Pratap, J., Gaur, T., Grigoriu, S., Ali, S. A., Stein, J. L., Lian, J. B., Van Wijnen, A. J., & Stein, G. S. (2007). Runx2 deficiency and defective subnuclear targeting bypass senescence to promote immortalization and tumorigenic potential. Proceedings of the National Academy of Sciences of the United States of America, 104(50), 19861-19866. https://doi.org/10.1073/pnas.0709650104