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首页> 外文期刊>Journal of cellular biochemistry. >Glucose-activated RUNX2 phosphorylation promotes endothelial cell proliferation and an angiogenic phenotype.
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Glucose-activated RUNX2 phosphorylation promotes endothelial cell proliferation and an angiogenic phenotype.

机译：葡萄糖激活的RUNX2磷酸化促进内皮细胞增殖和血管生成表型。

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摘要

The runt-related protein-2 (RUNX2) is a DNA-binding transcription factor that regulates bone formation, tumor cell metastasis, endothelial cell (EC) proliferation, and angiogenesis. RUNX2 DNA binding is glucose and cell cycle regulated. We propose that glucose may activate RUNX2 through changes in post-translational phosphorylation that are cell cycle-specific and will regulate EC function. Glucose increased cell cycle progression in EC through both G2/M and G1 phases with entry into S-phase occurring only in subconfluent cells. In the absence of nutrients and growth factors (starvation), subconfluent EC were delayed in G1 when RUNX2 expression was reduced. RUNX2 phosphorylation, activation of DNA binding, and pRb phosphorylation were stimulated by glucose and were necessary to promote cell cycle progression. Glucose increased RUNX2 localization at focal subnuclear sites, which co-incided with RUNX2 occupancy of the cyclin-dependent kinase (cdk) inhibitor p21(Cip1) promoter, a gene normally repressed by RUNX2. Mutation of the RUNX2 cdk phosphorylation site in the C-terminal domain (S451A.RUNX2) reduced RUNX2 phosphorylation and DNA binding. Expression of this cdk site mutant in EC inhibited glucose-stimulated differentiation (in vitro tube formation), monolayer wound healing, and proliferation. These results define a novel relationship between glucose-activated RUNX2 phosphorylation, cell cycle progression, and EC differentiation. These data suggest that inhibition of RUNX2 expression or DNA binding may be a useful strategy to inhibit EC proliferation in tumor angiogenesis.
机译：矮子相关蛋白2（RUNX2）是一种DNA结合转录因子，可调节骨骼形成，肿瘤细胞转移，内皮细胞（EC）增殖和血管生成。 RUNX2 DNA结合受葡萄糖和细胞周期的调节。我们建议葡萄糖可以通过翻译后磷酸化的改变激活RUNX2，这些改变是细胞周期特异性的，并且将调节EC功能。葡萄糖通过G2 / M和G1期增加EC中的细胞周期进程，进入S期仅在亚融合细胞中发生。在缺乏营养和生长因子（饥饿）的情况下，当RUNX2表达降低时，G1中的亚融合EC延迟。葡萄糖刺激RUNX2磷酸化，DNA结合激活和pRb磷酸化，这对于促进细胞周期进程是必需的。葡萄糖增加了RUNX2在局灶性亚核部位的定位，这与细胞周期蛋白依赖性激酶（cdk）抑制剂p21（Cip1）启动子（通常受RUNX2抑制的基因）的RUNX2占有率同时发生。 C末端域中的RUNX2 cdk磷酸化位点的突变（S451A.RUNX2）减少了RUNX2磷酸化和DNA结合。该cdk位点突变体在EC中的表达抑制了葡萄糖刺激的分化（体外管形成），单层伤口愈合和增殖。这些结果定义了葡萄糖激活的RUNX2磷酸化，细胞周期进程和EC分化之间的新型关系。这些数据表明，抑制RUNX2表达或DNA结合可能是在肿瘤血管生成中抑制EC增殖的有用策略。

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