Department of Periodontics and Oral Medicine, University of Michigan, School of Dentistry, Ann Arbor, MI 48109-1078, USA.
Mol Cell Biochem. 2010 Oct;343(1-2):201-9. doi: 10.1007/s11010-010-0514-6. Epub 2010 Jun 26.
The extracellular matrix (ECM) plays a key role in cell-cell communication and signaling, and the signals it propagates are important for tissue remodeling and survival. However, signals from disease-altered ECM may lead to anoikis-apoptotic cell death triggered by loss of ECM contacts. Previously, we found that an altered fibronectin matrix triggers anoikis in human primary ligament cells via a pathway that requires p53 transcriptional downregulation. Here we show that this p53 reduction is suppressed by transfecting cells with Mdm2 antisense oligonucleotides or small interfering RNA. Similar results were found in cells treated to prevent p53 and Mdm2 interactions. When p53 was overexpressed in cells lacking Mdm2 and p53, p53 levels were unaffected by anoikis conditions. However, cells cotransfected with p53 and wild type Mdm2, but not a mutant Mdm2, exhibited decreased p53 levels in response to anoikis conditions. Thus, cells under anoikis conditions undergo p53 degradation that is mediated by Mdm2.
细胞外基质 (ECM) 在细胞间通讯和信号转导中起着关键作用，它传递的信号对于组织重塑和存活很重要。然而，疾病改变的 ECM 产生的信号可能导致细胞因失去 ECM 接触而发生凋亡。此前，我们发现改变的纤维连接蛋白基质通过需要 p53 转录下调的途径引发人原代韧带细胞发生凋亡。在这里，我们表明，通过转染细胞用 Mdm2 反义寡核苷酸或小干扰 RNA 可以抑制这种 p53 减少。在防止 p53 和 Mdm2 相互作用的细胞中也发现了类似的结果。当细胞中过表达缺乏 Mdm2 和 p53 的 p53 时，p53 水平不受凋亡条件的影响。然而，共转染 p53 和野生型 Mdm2 的细胞，但不是突变型 Mdm2，在凋亡条件下表现出 p53 水平降低。因此，凋亡条件下的细胞经历由 Mdm2 介导的 p53 降解。
