Zaidi Sayyed K, Pande Sandhya, Pratap Jitesh, Gaur Tripti, Grigoriu Simina, Ali Syed A, Stein Janet L, Lian Jane B, van Wijnen Andre J, Stein Gary S
Department of Cell Biology and Cancer Center, University of Massachusetts Medical School and Cancer Center, 55 Lake Avenue North, Worcester, MA 01655, USA.
Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):19861-6. doi: 10.1073/pnas.0709650104. Epub 2007 Dec 5.
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.
成骨相关的Runt转录因子（Runx2）在正常二倍体成骨细胞中负向调节增殖和核糖体基因表达，但在转移性乳腺癌和前列腺癌细胞中上调。因此，Runx2可能根据细胞环境发挥肿瘤抑制因子或癌基因的作用。在此我们表明，Runx2缺陷的原代成骨细胞无法经历衰老，这表现为缺乏β-半乳糖苷酶活性和p16（INK4a）肿瘤抑制因子表达。原代Runx2基因敲除的成骨细胞具有生长优势，并表现出p21（WAF1/CIP1）和p19（ARF）表达缺失。重新引入野生型Runx2，而非亚核靶向缺陷突变体，可诱导p21（WAF/CIP1）和p19（ARF）的mRNA及蛋白表达，从而导致细胞周期抑制。自发磷酸化H2A.X灶的积累、端粒完整性丧失以及Mre11/Rad50/Nbs1 DNA修复复合物的缺失，还有延迟的DNA修复反应均表明Runx2缺陷会导致基因组不稳定。我们提出Runx2在原代二倍体成骨细胞中发挥肿瘤抑制因子的作用，并且亚核靶向有助于Runx2介导的肿瘤抑制。
