From the San Diego State University Heart Institute and Biology Department, San Diego State University, San Diego, California 92182 and.
J Biol Chem. 2014 Feb 28;289(9):5348-56. doi: 10.1074/jbc.M113.526442. Epub 2013 Dec 27.
Autologous c-kit(+) cardiac progenitor cells (CPCs) are currently used in the clinic to treat heart disease. CPC-based regeneration may be further augmented by better understanding molecular mechanisms of endogenous cardiac repair and enhancement of pro-survival signaling pathways that antagonize senescence while also increasing differentiation. The prolyl isomerase Pin1 regulates multiple signaling cascades by modulating protein folding and thereby activity and stability of phosphoproteins. In this study, we examine the heretofore unexplored role of Pin1 in CPCs. Pin1 is expressed in CPCs in vitro and in vivo and is associated with increased proliferation. Pin1 is required for cell cycle progression and loss of Pin1 causes cell cycle arrest in the G1 phase in CPCs, concomitantly associated with decreased expression of Cyclins D and B and increased expression of cell cycle inhibitors p53 and retinoblastoma (Rb). Pin1 deletion increases cellular senescence but not differentiation or cell death of CPCs. Pin1 is required for endogenous CPC response as Pin1 knock-out mice have a reduced number of proliferating CPCs after ischemic challenge. Pin1 overexpression also impairs proliferation and causes G2/M phase cell cycle arrest with concurrent down-regulation of Cyclin B, p53, and Rb. Additionally, Pin1 overexpression inhibits replicative senescence, increases differentiation, and inhibits cell death of CPCs, indicating that cell cycle arrest caused by Pin1 overexpression is a consequence of differentiation and not senescence or cell death. In conclusion, Pin1 has pleiotropic roles in CPCs and may be a molecular target to promote survival, enhance repair, improve differentiation, and antagonize senescence.
自体 c-kit(+) 心脏祖细胞 (CPCs) 目前用于临床治疗心脏病。通过更好地了解内源性心脏修复的分子机制，并增强抗衰老的促生存信号通路，CPC 为基础的再生可能会进一步增强，同时还增加分化。脯氨酰异构酶 Pin1 通过调节蛋白质折叠，从而调节磷酸化蛋白的活性和稳定性，调节多个信号级联。在这项研究中，我们研究了 Pin1 在 CPCs 中的迄今尚未探索的作用。Pin1 在体外和体内的 CPCs 中表达，并与增殖增加有关。Pin1 是细胞周期进程所必需的，Pin1 的缺失导致 CPCs 中的细胞周期停滞在 G1 期，同时伴随着细胞周期蛋白 D 和 B 的表达减少和细胞周期抑制剂 p53 和视网膜母细胞瘤 (Rb) 的表达增加。Pin1 的缺失增加了细胞衰老，但不会增加 CPCs 的分化或细胞死亡。Pin1 是内源性 CPC 反应所必需的，因为 Pin1 敲除小鼠在缺血性挑战后增殖的 CPCs 数量减少。Pin1 过表达也会损害增殖，并导致 G2/M 期细胞周期停滞，同时下调细胞周期蛋白 B、p53 和 Rb。此外，Pin1 过表达抑制复制性衰老，增加 CPCs 的分化，并抑制细胞死亡，表明 Pin1 过表达引起的细胞周期停滞是分化的结果，而不是衰老或细胞死亡。总之，Pin1 在 CPCs 中具有多种作用，可能是促进生存、增强修复、改善分化和拮抗衰老的分子靶点。
