Hua Guoqiang, Wang Shuo, Zhong Chao, Xue Peng, Fan Zusen
National Laboratory of Biomacromolecules and Center for Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
J Immunol. 2009 Feb 15;182(4):2152-9. doi: 10.4049/jimmunol.0802307.
Inactivation of tumor suppressor p53 results in loss of the apoptosis-regulating function of the p53 protein in tumor cells. Restoration of wild-type p53 expression in p53 mutant tumor cells increases tumor susceptibility to CTL-mediated cytolysis. However, the direct role of p53 in regulating tumor sensitivity to NK cell-mediated lysis and the functional relationship between p53 and granzymes in the control of tumor killing are still poorly documented. In this study, we found that p53 can sensitize tumor-killing susceptibility to NK and granzyme K-mediated cytolysis. Granzyme K is constitutively expressed in high levels in NK cells and induces rapid caspase-independent cell death. Granzyme K may exert a critical role in NK cell-mediated tumor clearance. p53 associates with granzyme K and is a physiological substrate of granzyme K. p53 was processed to three cleavage products of p40, p35, and p13 fragments at Lys(24) and Lys(305). These three cleavage products harbor strong proapoptotic activities that amplify the proapoptotic action of p53 to potentiate tumor-killing sensitivity. Therefore, p53 is as a cytotoxic bomb that can be triggered by granzyme K, leading to potentiating killing efficacy.
肿瘤抑制因子p53的失活导致肿瘤细胞中p53蛋白的凋亡调节功能丧失。在p53突变肿瘤细胞中恢复野生型p53表达可增加肿瘤对CTL介导的细胞溶解的敏感性。然而，p53在调节肿瘤对NK细胞介导的裂解的敏感性方面的直接作用以及p53与颗粒酶在控制肿瘤杀伤中的功能关系仍鲜有报道。在本研究中，我们发现p53可使肿瘤对NK和颗粒酶K介导的细胞溶解的杀伤敏感性增强。颗粒酶K在NK细胞中持续高水平表达，并诱导快速的非半胱天冬酶依赖性细胞死亡。颗粒酶K可能在NK细胞介导的肿瘤清除中发挥关键作用。p53与颗粒酶K结合，是颗粒酶K的生理底物。p53在赖氨酸（24）和赖氨酸（305）处被加工成p40、p35和p13片段这三种裂解产物。这三种裂解产物具有强大的促凋亡活性，可放大p53的促凋亡作用，从而增强肿瘤杀伤敏感性。因此，p53就像一枚可被颗粒酶K触发的细胞毒性炸弹，导致杀伤效力增强。
