Quan Taihao, Shao Yuan, Purohit Trupta, Jiang Yiou, Qin Zhaoping, Fisher Gary J, Lents Nathan H, Baldassare Joseph J
Department of Dermatology University of Michigan Medical School Ann Arbor Michigan USA.
Department of Pharmacological Sciences at Saint Louis University St. Louis Missouri USA.
J Cell Commun Signal. 2025 Feb 1;19(1):e70003. doi: 10.1002/ccs3.70003. eCollection 2025 Mar.
CCN2 is widely regarded as a profibrotic factor involved in fibrotic disorders by regulating extracellular matrix (ECM). We report here that CCN2 functions as a critical cell cycle regulator in primary human dermal fibroblasts (HDFs). siRNA-mediated knockdown of CCN2 halted proliferation of primary HDFs, which was rescued by a siRNA-resistant CCN2 expression vector. Furthermore, CCN2 knockdown caused a significant accumulation of cells in G1/G0 phase and blocked entry into S-phase. Mechanistically, CCN2 knockdown blocked cyclin E and CDK4/cyclin D nuclear translocation, and abrogated CDK2 activity. Markedly, CCN2 translocated to the nucleus and co-localized with cyclin D1 upon cell cycle stimulation. Finally, we show that CCN2, a bona fide YAP/TAZ target gene, partially mediates YAP/TAZ-dependent proliferation of primary HDFs. These data provide evidence of a novel CCN2 function as a cell cycle regulator in primary HDFs proliferation, in addition to its known role in ECM regulation.
CCN2被广泛认为是一种通过调节细胞外基质（ECM）参与纤维化疾病的促纤维化因子。我们在此报告，CCN2在原代人皮肤成纤维细胞（HDFs）中作为关键的细胞周期调节因子发挥作用。siRNA介导的CCN2敲低使原代HDFs的增殖停止，而siRNA抗性的CCN2表达载体可挽救这种增殖。此外，CCN2敲低导致细胞在G1/G0期显著积累，并阻止进入S期。机制上，CCN2敲低阻断了细胞周期蛋白E和CDK4/细胞周期蛋白D的核转位，并消除了CDK2活性。值得注意的是，在细胞周期刺激下，CCN2转位至细胞核并与细胞周期蛋白D1共定位。最后，我们表明CCN2作为一种真正的YAP/TAZ靶基因，部分介导了原代HDFs的YAP/TAZ依赖性增殖。这些数据提供了证据，证明CCN2除了在ECM调节中的已知作用外，在原代HDFs增殖中作为细胞周期调节因子具有新功能。
