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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2007-12, Vol.104 (50), p.19861-19866
• Main Authors: Zaidi, Sayyed K, Pande, Sandhya, Pratap, Jitesh, Gaur, Tripti, Grigoriu, Simina, Ali, Syed A, Stein, Janet L, Lian, Jane B, van Wijnen, Andre J, Stein, Gary S
• Format: Article
• Language: English
• Subjects: Animals; Biological Sciences; Cancer; Cell growth; Cell Nucleus - genetics; Cell Nucleus - metabolism; Cell Proliferation; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Cells; Cells, Cultured; Cellular senescence; Cellular Senescence - genetics; Core Binding Factor Alpha 1 Subunit - deficiency; Core Binding Factor Alpha 1 Subunit - genetics; Core Binding Factor Alpha 1 Subunit - metabolism; Core Binding Factor Alpha 1 Subunit - physiology; Cyclin-Dependent Kinase Inhibitor p21 - physiology; Diploidy; DNA damage; DNA repair; Gene Targeting; Genomic instability; Genomic Instability - physiology; Mice; Mice, Knockout; Osteoblasts; Osteoblasts - metabolism; Osteoblasts - pathology; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0709650104

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 p19ARF expression. Reintroduction of WT Runx2, but not a subnuclear targeting-defective mutant, induces both p21WAF/CIP¹ and p19ARF 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.