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Ignition of p53 Bomb Sensitizes Tumor Cells to Granzyme K-Mediated Cytolysis¹

National Laboratory of Biomacromolecules and Center for Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China

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 Lys²⁴ and Lys³⁰⁵. 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.

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¹ This work was supported by the National Natural Science Foundation of China (Grants 30525005, 30830030, and 30528028), 863 Program (2006AA02Z4C9), 973 Programs (2006CB504303, 2006CB910901), the Innovative Program (KSCX2-YW-R-42), and the Hundred Talents Program of the Chinese Academy of Science (to Z.F.).

² Address correspondence and reprint requests to Dr. Zusen Fan, National Laboratory of Biomacromolecules and Center for Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China. E-mail address: fanz{at}moon.ibp.ac.cn

³ Abbreviations used in this paper: Gzm, granzyme; mGzmK, mutated GzmK; Ad, adenovirus; ROS, reactive oxygen species; HA, hemagglutinin; CMA, concanamycin A; PI, propidium iodide; RT, room temperature; S-AGzmK, Ser-Ala GzmK.