Bone Cell Growth Regulation by Runx2/Cbfa1

我们已经取得了重要发现，成骨细胞成熟促进转录因子Runx2控制成骨前细胞的细胞周期进程，并且通过细胞周期的进程通过转录和转录后机制在三个不同的细胞周期阶段（即G0/G1， G1/S和M/G1过渡）调节Runx2的活性。Runx2在有丝分裂过程中发挥关键的表观遗传功能，当正常成骨细胞监测细胞外信号以启动细胞周期进程时，Runx2在G1早期表达。我们认为，正常成骨细胞中Runx2的选择性蛋白水解降解对于Runx2进入S期前的急性下调至关重要。

We have made the key discoveries that Runx2, the osteoblast maturation promoting transcription factor, controls cell cycle progression in pre-osteoblastic cells, and progression through the cell cycle modulates Runx2 activity at three different cell cycle stages (i.e., the G0/G1, G1/S and M/G1 transitions) by both transcriptional and post-transcriptional mechanisms. Runx2 performs a critical epigenetic function during mitosis and its expression in early G1 occurs when normal osteoblasts monitor extracellular cues for competency to initiate cell cycle progression. We propose that selective proteolytic degradation of Runx2 in normal osteoblasts is critical for acute downregulation of Runx2 prior to entry into S phase. The central hypothesis of our proposal is that Runx2 peptide motifs (Specific Aim 1) and ubiquitination of Runx2 (Specific Aim 2) mediate its selective degradation during late G1 in the osteoblast cell cycle to prevent cell growth suppression through activation of a putative cell cycle checkpoint. Specific Aim 1 will examine what Runx2 peptide motifs, which represent part of a putative molecular relay that stages protein/protein interactions, are required for Runx2 degradation. Specific Aim 2 will identify the E3 ubiquitin ligase that destabilizes Runx2 and characterize novel osteoblast-related co-factors (e.g., F-box proteins) that support ubiquitin ligation.