Runx2 deficiency and defective subnuclear targeting bypass senescence to promote immortalization and tumorigenic potential
Department of Cell Biology
Medical Subject Headings
Animals; Cell Aging; Cell Nucleus; Cell Proliferation; Cell Transformation, Neoplastic; Cells, Cultured; Core Binding Factor Alpha 1; Subunit; Cyclin-Dependent Kinase Inhibitor p21; Gene Targeting; Genomic Instability; Mice; Mice, Knockout; Osteoblasts
Cancer Biology | Cell Biology | Life Sciences | Medicine and Health Sciences
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 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.
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Citation: Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):19861-6. Epub 2007 Dec 5. Link to article on publisher's site
Proceedings of the National Academy of Sciences of the United States of America
Zaidi, Sayyed K.; Pande, Sandhya; Pratap, Jitesh; Gaur, Tripti; Grigoriu, Simina R.; Ali, Syed A.; Stein, Janet L.; Lian, Jane B.; Van Wijnen, Andre J.; and Stein, Gary S., "Runx2 deficiency and defective subnuclear targeting bypass senescence to promote immortalization and tumorigenic potential" (2007). GSBS Student Publications. 349.