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Runx2 deficiency and defective subnuclear targeting bypass senescence to promote immortalization and tumorigenic
Sayyed K Zaidi1, Sandhya Pande, Jitesh Pratap
1Department of Cell Biology and Cancer Center, University of Massachusetts Medical School and Cancer Center, 55 Lake Avenue North, Worcester, MA 01655, USA.
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 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.
Insights
The Runt-related transcription factor (Runx2) acts as a tumor suppressor in osteoblasts, preventing uncontrolled cell growth and maintaining genomic stability. Its absence leads to senescence defects and DNA repair issues.
Area of Science:
- Molecular Biology
- Cancer Biology
- Cell Biology
Background:
- The Runt-related transcription factor 2 (Runx2) plays a dual role in cell proliferation and gene expression, acting as a tumor suppressor in normal osteoblasts but an oncogene in metastatic cancers.
- The context-dependent function of Runx2 necessitates further investigation into its specific roles in different cellular environments.
Purpose of the Study:
- To investigate the role of Runx2 in osteoblast senescence and genomic stability.
- To determine if Runx2 functions as a tumor suppressor in primary diploid osteoblasts.
- To elucidate the mechanism by which Runx2 regulates cell-cycle inhibition and DNA repair.
Main Methods:
- Analysis of Runx2-deficient primary osteoblasts for senescence markers (beta-gal activity, p16INK4a).
- Assessment of cell proliferation, p21WAF1/CIP1, and p19ARF expression in Runx2-null and reconstituted osteoblasts.
- Evaluation of genomic instability through phospho-H2A.X foci, telomere integrity, DNA repair complex assessment, and DNA repair response timing.
Main Results:
- Runx2 deficiency abrogates osteoblast senescence, characterized by absent beta-gal activity and p16INK4a expression.
- Runx2-null osteoblasts exhibit enhanced proliferation and reduced expression of cell-cycle inhibitors p21WAF1/CIP1 and p19ARF.
- Reintroduction of wild-type Runx2, but not a mutant lacking subnuclear targeting, restores cell-cycle inhibition.
- Runx2 deficiency causes genomic instability, evidenced by DNA damage accumulation, telomere dysfunction, impaired DNA repair, and delayed repair responses.
Conclusions:
- Runx2 functions as a tumor suppressor in primary diploid osteoblasts by inhibiting proliferation and maintaining genomic stability.
- Subnuclear targeting is a critical mechanism for Runx2-mediated tumor suppression.
- Dysregulation of Runx2 contributes to genomic instability and potentially cancer development in osteoblasts.
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