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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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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.