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Adaptor Protein LAPF Recruits Phosphorylated p53 to Lysosomes and Triggers Lysosomal Destabilization in Apoptosis

¹ Institute of Immunology and National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai, P.R. China and ² Institute of Immunology, Zhejiang University, Hangzhou, Zhejiang, P.R. China

Requests for reprints: Xuetao Cao, Institute of Immunology and National Key Laboratory of Medical Immunology, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, P.R. China. Phone: 86-21-5562-0605; Fax: 86-21-6538-2502; E-mail: caoxt{at}public3.sta.net.cn.

Evidence suggests a functional association between the tumor suppressor p53 and apoptosis-involved organelle lysosome; however, the detailed mechanisms remain poorly understood. We recently reported that a lysosome-targeting protein, LAPF (lysosome-associated and apoptosis-inducing protein containing PH and FYVE domains), could initiate apoptosis of L929 cells through a lysosomal-mitochondrial pathway. In this study, we show that LAPF specifically interacted with phosphorylated p53 (Ser^15/18) both in vitro and in vivo, which could be enhanced by apoptotic stimuli, such as tumor necrosis factor (TNF-) and ionizing irradiation. The PH domain of LAPF and the transactivation domain of p53 mediated the interaction between both molecules. Phosphorylated p53 (Ser^15/18) could translocate to lysosomes before lysosomal membrane permeabilization (LMP) in LAPF-initiated and TNF-induced apoptosis. Silencing of LAPF expression abrogated lysosomal translocation of phosphorylated p53 (Ser^15/18), whereas silencing of p53 expression had no effect on lysosomal translocation of LAPF. Similar to that of LAPF silencing, silencing of endogenous p53 expression in L929 cells could significantly impair TNF-–induced LMP and apoptosis. However, reexpression of wild-type p53, p53S15D (substitution of Ser¹⁵ to Asp that mimics a phosphorylated state), and p53R175H (a transcription-deficient mutant) in p53-knockdown L929 cells could rescue the decrease in TNF-induced apoptosis. The data suggest that phosphorylated p53 (Ser^15/18) might translocate to lysosome via forming complexes with adaptor protein LAPF and subsequently result in LMP and apoptosis, which might be in a transcription-independent manner. [Cancer Res 2007;67(23):11176–85]