Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago College of Medicine, Chicago, IL 60607-7170, USA.
Nat Cell Biol. 2010 Jul;12(7):676-85. doi: 10.1038/ncb2070. Epub 2010 Jun 6.
Cellular senescence is a recognized mechanism of tumour suppression; however, its contribution to other pathologies is not well understood. We show that the matricellular protein CCN1 (also known as CYR61; cysteine-rich protein 61), which is dynamically expressed at sites of wound repair, can induce fibroblast senescence by binding to integrin alpha(6)beta(1) and the heparan sulphate proteoglycans (receptors involved in cell adhesion). CCN1 induces DNA damage response pathways and activates p53 and the RAC1-NOX1 complex, which generates reactive oxygen species (ROS). This results in the ROS-dependent activation of the p16(INK4a)/pRb pathway, leading to senescence and concomitant expression of antifibrotic genes. Senescent fibroblasts accumulate in granulation tissues of healing cutaneous wounds and express antifibrotic genes in wild-type mice. These processes are lost in knockin mice that express a senescence-defective Ccn1 mutant, resulting in exacerbated fibrosis. Topical application of CCN1 protein to wounds reverses these defects. Thus, fibroblast senescence is a CCN1-dependent wound healing response in cutaneous injury that functions to curb fibrosis during tissue repair.
细胞衰老被认为是肿瘤抑制的一种机制，但它对其他病理的贡献还不是很清楚。我们发现，细胞基质蛋白 CCN1（也称为 CYR61；富含半胱氨酸的蛋白 61）在伤口修复部位动态表达，可通过与整合素 α6β1 和硫酸乙酰肝素蛋白聚糖（参与细胞黏附的受体）结合，诱导成纤维细胞衰老。CCN1 可诱导 DNA 损伤反应途径，并激活 p53 和 RAC1-NOX1 复合物，产生活性氧（ROS）。这导致 ROS 依赖性激活 p16(INK4a)/pRb 途径，导致衰老和伴随的抗纤维化基因表达。衰老的成纤维细胞在愈合的皮肤伤口的肉芽组织中积累，并在野生型小鼠中表达抗纤维化基因。这些过程在表达衰老缺陷性 Ccn1 突变体的敲入小鼠中丢失，导致纤维化加剧。CCN1 蛋白的局部应用于伤口可逆转这些缺陷。因此，成纤维细胞衰老可能是皮肤损伤中一种依赖 CCN1 的伤口愈合反应，它可在组织修复过程中抑制纤维化。
