GSBS Student Publications

Title

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

Student Author(s)

Sandhya Pande

GSBS Program

Cell Biology

Publication Date

2007-12-14

UMMS Affiliation

Department of Cell Biology

Document Type

Article

Disciplines

Cancer Biology | Cell Biology | Life Sciences | Medicine and Health Sciences

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.

DOI of Published Version

10.1073/pnas.0709650104

Source

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

Journal/Book/Conference Title

Proceedings of the National Academy of Sciences of the United States of America

Related Resources

Link to Article in PubMed

PubMed ID

18077419

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