Runx2 deficiency and defective subnuclear targeting bypass senescence to promote immortalization and tumorigenic potential
AuthorsZaidi, Sayyed K.
Grigoriu, Simina R.
Ali, Syed A.
Stein, Janet L.
Lian, Jane B.
Van Wijnen, Andre J.
Stein, Gary S.
Student AuthorsSandhya Pande
UMass Chan AffiliationsDepartment of Cell Biology
Document TypeJournal Article
KeywordsAnimals; 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
Medicine and Health Sciences
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AbstractThe 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.
SourceProc Natl Acad Sci U S A. 2007 Dec 11;104(50):19861-6. Epub 2007 Dec 5. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/33684
Related ResourcesLink to Article in PubMed