Runx2 deficiency and defective subnuclear targeting bypass senescence to promote immortalization and tumorigenic potential.
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.
Zaidi
Sayyed K
SK
Department of Cell Biology and Cancer Center, University of Massachusetts Medical School and Cancer Center, 55 Lake Avenue North, Worcester, MA 01655, USA.
Pande
Sandhya
S
Pratap
Jitesh
J
Gaur
Tripti
T
Grigoriu
Simina
S
Ali
Syed A
SA
Stein
Janet L
JL
Lian
Jane B
JB
van Wijnen
Andre J
AJ
Stein
Gary S
GS
D000818:Animals; D002467:Cell Nucleus / Q000235:genetics* / Q000378:metabolism*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics*; D050659:Core Binding Factor Alpha 1 Subunit / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000502:physiology; D018390:Gene Targeting; D042822:Genomic Instability / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology
C493957:Cdkn1a protein, mouse; D050659:Core Binding Factor Alpha 1 Subunit; D050759:Cyclin-Dependent Kinase Inhibitor p21; C493716:Runx2 protein, mouse