保持基因组的稳定性需要DNA的精确复制。真核细胞通过G1期DNA复制执照因子在复制起点处形成复制前复合体，并在细胞周期其余阶段通过蛋白酶体降解执照因子保证DNA在一轮细胞周期中只复制一次。DNA复制执照因子的失调将导致基因组的不稳定性，进而诱导肿瘤的发生。在前列腺癌细胞中雄激素受体AR发挥DNA复制执照因子的功能，经过M期降解从而允许下一轮细胞周期DNA复制起始。研究发现在M期稳定AR蛋白就会阻滞前列腺癌细胞的生长。已知AR蛋白在M期降解是通过蛋白酶体通路实现的，但具体的调控机制并不清楚。PC-1基因在前列腺癌细胞特异性表达，我们前期研究发现该基因在细胞周期G2/M期高表达；可以和AR蛋白相互作用并调控AR的稳定性；可以和调控AR的E3连接酶CHIP相互作用并增强其和AR的相互作用。本项目将研究PC-1在M期和CHIP共同作用调控AR降解的分子机制，深入了解AR在前列腺癌进展中的功能。

Maintenance of genomic stability requires accurate DNA replication. Eukaryotic cells achieve this through recruiting the licensing factors to the origins and the assembly of prereplication complexes at origins during the G1 phase of the cell cycle and subsequently by 26S proteasome-mediated degradation of the licensing actors to prevent DNA re-replication. The dysregulation of DNA replication licensing factors will contribute to the genomic instability and oncogenesis. A newly emerging role of AR (Androgen Receptor) in prostate cancer is functioning as a component of DNA replication licensing factors, which are degraded during mitosis and allow relicensing only at the next cycle. A recent study showed that stabilizing AR in mitosis inhibits prostate cancer cell growth. Although it is known degradation of AR occurs primarily through a proteasome-dependent pathway, very little is known about how this process is regulated. PC-1 gene is expressed specificity in prostate cancer and higher expression at G2/M; PC-1 can interact with AR and E3 ligase CHIP (Carboxy terminus of Hsc70 Interacting Protein) , at the same time enhance the interaction of AR with CHIP and regulate the stability of AR. This project aims to investigate the mechanism of PC-1 in cooperation with E3 ligase CHIP coregulate the stability of AR in M phase of cell cycle and the role of AR as a DNA replication factor in the development of prostate cancer.

保持基因组的稳定性需要DNA的精确复制。真核细胞通过G1期DNA复制执照因子在复制起点处形成复制前复合体，并在细胞周期其余阶段通过蛋白酶体降解执照因子保证DNA在一轮细胞周期中只复制一次。DNA复制执照因子的失调将导致基因组的不稳定性，进而诱导肿瘤的发生。在前列腺癌细胞中雄激素受体AR（Androgen Receptor）发挥DNA复制执照因子的功能，经过M期降解从而允许下一轮细胞周期DNA复制起始。研究发现在M期稳定AR蛋白就会阻滞前列腺癌细胞的生长。已知AR蛋白在M期降解是通过蛋白酶体通路实现的，但具体的调控机制并不清楚。PC-1是雄激素应答因子，在前列腺癌中表达特异性，在G2 / M处有较高的表达。在此研究中，PC-1显示与AR和E3连接酶CHIP（Hsc70相互作用蛋白的羧基末端）相互作用并增强AR / CHIP相互作用，从而降低AR稳定性。此外，我们研究发现PC-1与CHIP一起通过泛素化作用，在细胞周期的M期通过降低AR蛋白质水平而起作用。我们的研究还发现PC-1在雄激素依赖性和雄激素非依赖性前列腺癌细胞中抑制AR转录活性并减弱AR的生长抑制。总之，这些发现提供了关于通过PC-1调节AR稳定性的新线索，并揭示了PC-1在AR信号中的重要作用。