Metabolic regulation of the CCN family genes by glycolysis in chondrocytes
Metabolic regulation of the CCN family genes by glycolysis in chondrocytes
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DOI：
10.1007/s12079-017-0420-8
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发表时间：
2018-03-01
影响因子：
4.1
通讯作者：
Kubota, Satoshi
中科院分区：
文献类型：
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作者：
Akashi, Sho;Nishida, Takashi;Kubota, Satoshi
CCN家族由哺乳动物基因组中的6个基因组成，产生参与多种生物过程的多功能蛋白质。最近的报告表明 CCN2 在软骨细胞能量代谢中的深远作用，并且已知 Ccn2 缺陷会改变包括 Ccn3 在内的其他 2 个家族成员的表达。然而，关于CCN家族基因通过能量代谢的调节几乎一无所知。为了深入了解这个关键问题，我们初步全面评估了糖酵解抑制对软骨细胞中所有 CCN 家族基因表达的影响。抑制糖酵解酶后，观察到 CCN2 表达受到抑制，而 CCN3 表达则相反被诱导。有氧 ATP 产生的抑制也对 CCN2 产生类似的抑制，然而，这不会诱导 CCN3 的表达。相反，葡萄糖饥饿显着增强了这些细胞中 CCN3 的表达。使用含有 CCN3 近端启动子的分子构建体进行的报告基因测定结果显示，软骨细胞中糖酵解抑制剂对 CCN3 启动子活性的诱导呈剂量依赖性。这些结果揭示了糖酵解活性在 CCN2 和 CCN3 调节中的关键作用，该活性介导软骨细胞中这两个主要 CCN 家族成员的相互调节。
The CCN family consists of 6 genes in the mammalian genome and produces multifunctional proteins involved in a variety of biological processes. Recent reports indicate the profound roles of CCN2 in energy metabolism in chondrocytes, and Ccn2 deficiency is known to alter the expression of 2 other family members including Ccn3. However, almost nothing is known concerning the regulation of the CCN family genes by energy metabolism. In order to gain insight into this critical issue, we initially and comprehensively evaluated the effect of inhibition of glycolysis on the expression of all of the CCN family genes in chondrocytic cells. Upon the inhibition of a glycolytic enzyme, repression of CCN2 expression was observed, whereas CCN3 expression was conversely induced. Similar repression of CCN2 was conferred by the inhibition of aerobic ATP production, which, however, did not induce CCN3 expression. In contrast, glucose starvation significantly enhanced the expression of CCN3 in those cells. The results of a reporter gene assay using a molecular construct containing a CCN3 proximal promoter revealed a dose-dependent induction of the CCN3 promoter activity by the glycolytic inhibitor in chondrocytic cells. These results unveiled a critical role of glycolytic activity in the regulation of CCN2 and CCN3, which activity mediated the mutual regulation of these 2 major CCN family members in chondrocytes.