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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 and Gary S. Stein
Proceedings of the National Academy of Sciences of the United States of America
Vol. 104, No. 50 (Dec. 11, 2007), pp. 19861-19866
Stable URL: http://www.jstor.org/stable/25450807
Page Count: 6
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Since scans are not currently available to screen readers, please contact JSTOR User Support for access. We'll provide a PDF copy for your screen reader.
Runx2 Deficiency and Defective Subnuclear Targeting Bypass Senescence to Promote Immortalization and Tumorigenic Potential
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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 ${\rm p}16^{{\rm INK}4{\rm a}}$ tumor suppressor expression. Primary Runx2-null osteoblasts have a growth advantage and exhibit loss of ${\rm p}21^{{\rm WAF}1/{\rm CIP}1}$ and ${\rm p}19^{{\rm ARF}}$ expression. Reintroduction of WT Runx2, but not a subnuclear targeting-defective mutant, induces both ${\rm p}21^{{\rm WAF}/{\rm CIP}1}$ and ${\rm p}19^{{\rm ARF}}$ 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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