衔接蛋白LAPF将磷酸化的p53募集至溶酶体，并触发细胞凋亡中的溶酶体去稳定作用。,Cancer Research

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衔接蛋白LAPF将磷酸化的p53募集至溶酶体，并触发细胞凋亡中的溶酶体去稳定作用。
Cancer Research ( IF 12.5 ) Pub Date : 2007 Dec 1 , DOI: 10.1158/0008-5472.can-07-2333
Nan Li ₁ , Yuanyuan Zheng ₁ , Wei Chen ₂ , Chunmei Wang ₁ , Xingguang Liu ₁ , Weigang He ₂ , Hongmei Xu ₁ , Xuetao Cao _{1,

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Affiliation

有证据表明，抑癌基因p53与凋亡相关的细胞器溶酶体之间存在功能关联。但是，详细的机制仍然知之甚少。我们最近报道，靶向溶酶体的蛋白LAPF（溶酶体相关和凋亡诱导蛋白，含有PH和FYVE域）可以通过溶酶体-线粒体途径引发L929细胞凋亡。在这项研究中，我们表明LAPF在体外和体内均与磷酸化的p53（Ser（15/18））特异性相互作用，这可以通过凋亡刺激物（例如肿瘤坏死因子α（TNF-alpha）和电离辐射）来增强。LAPF的PH结构域和p53的反式激活结构域介导了两个分子之间的相互作用。磷酸化的p53（Ser（15/18））可能在LAPF启动和TNF诱导的细胞凋亡的溶酶体膜通透性（LMP）之前转位至溶酶体。LAPF表达的沉默消除了磷酸化的p53（Ser（15/18））的溶酶体易位，而p53表达的沉默对LAPF的溶酶体易位没有影响。与LAPF沉默类似，L929细胞中内源性p53表达的沉默可能显着损害TNF-α诱导的LMP和细胞凋亡。然而，在p53敲低的L929细胞中野生型p53，p53S15D（Ser（15）取代为模仿磷酸化状态的Asp）和p53R175H（转录缺陷型突变体）的重新表达可以挽救TNF诱导的凋亡的减少。。

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Adaptor protein LAPF recruits phosphorylated p53 to lysosomes and triggers lysosomal destabilization in apoptosis.

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 alpha (TNF-alpha) 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-alpha-induced LMP and apoptosis. However, reexpression of wild-type p53, p53S15D (substitution of Ser(15) 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.

更新日期：2017-01-31

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