Lysosomal-associated protein multispanning transmembrane 5 gene (LAPTM5) is associated with spontaneous regression of neuroblastomas.
Lysosomal-associated protein multispanning transmembrane 5 gene (LAPTM5) is associated with spontaneous regression of neuroblastomas.
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DOI：
10.1371/journal.pone.0007099
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发表时间：
2009-09-29
期刊：
影响因子：
3.7
通讯作者：
Inazawa J
中科院分区：
文献类型：
--
作者：
Inoue J;Misawa A;Tanaka Y;Ichinose S;Sugino Y;Hosoi H;Sugimoto T;Imoto I;Inazawa J
神经母细胞瘤（NB）是儿童最常见的实体瘤，具有异质性的临床表现。通常通过基于尿中儿茶酚胺水平增加的大规模筛查检测到的有利肿瘤通过程序性细胞死亡（PCD）自发消退或通过分化为良性神经节细胞瘤（GN）而成熟。相比之下，晚期NB肿瘤通常生长积极，尽管强化化疗。了解PCD的分子机制，在自然消退过程中有利的NB肿瘤，以及识别基因与促死亡的作用，是一个紧迫的问题，开发新的方法来治疗晚期NB肿瘤。我们发现，溶酶体相关蛋白多跨膜5（LAPTM 5）的表达通常是下调，由于DNA甲基化在NB细胞特异性的方式，但上调退化NB细胞内的局部退化地区的良好的肿瘤检测质量筛选。体外实验表明，不仅其表达的恢复，而且LAPTM 5蛋白的积累，诱导非凋亡性细胞死亡与自噬空泡和溶酶体不稳定与溶酶体膜透化（LMP）在半胱天冬酶非依赖性的方式。虽然自噬是降解溶酶体中蛋白质的膜运输途径，但LMP介导的LAPTM 5介导的溶酶体去稳定化导致自噬通量中断，导致不成熟自噬空泡、p62/SQSTM 1和泛素化蛋白作为自噬降解底物的积累。此外，泛素阳性包涵体出现在退化的NB细胞。我们提出了一种新的PCD分子机制，即由于LAPTM 5介导的溶酶体不稳定导致自噬空泡的积累。LAPTM 5诱导的细胞死亡是具有受损的自噬的溶酶体细胞死亡，而不是通过自噬的细胞死亡，所谓的自噬细胞死亡。因此，LAPTM 5介导的PCD与NB的自发消退密切相关，并为探索针对该肿瘤的创新临床干预开辟了新途径。
Neuroblastoma (NB) is the most frequently occurring solid tumor in children, and shows heterogeneous clinical behavior. Favorable tumors, which are usually detected by mass screening based on increased levels of catecholamines in urine, regress spontaneously via programmed cell death (PCD) or mature through differentiation into benign ganglioneuroma (GN). In contrast, advanced-type NB tumors often grow aggressively, despite intensive chemotherapy. Understanding the molecular mechanisms of PCD during spontaneous regression in favorable NB tumors, as well as identifying genes with a pro-death role, is a matter of urgency for developing novel approaches to the treatment of advanced-type NB tumors. We found that the expression of lysosomal associated protein multispanning transmembrane 5 (LAPTM5) was usually down-regulated due to DNA methylation in an NB cell-specific manner, but up-regulated in degenerating NB cells within locally regressing areas of favorable tumors detected by mass-screening. Experiments in vitro showed that not only a restoration of its expression but also the accumulation of LAPTM5 protein, was required to induce non-apoptotic cell death with autophagic vacuoles and lysosomal destabilization with lysosomal-membrane permeabilization (LMP) in a caspase-independent manner. While autophagy is a membrane-trafficking pathway to degrade the proteins in lysosomes, the LAPTM5-mediated lysosomal destabilization with LMP leads to an interruption of autophagic flux, resulting in the accumulation of immature autophagic vacuoles, p62/SQSTM1, and ubiqitinated proteins as substrates of autophagic degradation. In addition, ubiquitin-positive inclusion bodies appeared in degenerating NB cells. We propose a novel molecular mechanism for PCD with the accumulation of autophagic vacuoles due to LAPTM5-mediated lysosomal destabilization. LAPTM5-induced cell death is lysosomal cell death with impaired autophagy, not cell death by autophagy, so-called autophagic cell death. Thus LAPTM5-mediated PCD is closely associated with the spontaneous regression of NBs and opens new avenues for exploring innovative clinical interventions for this tumor.
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影响因子：
4.8
作者：
Karlsson, K;Carlsson, SR
通讯作者：
Carlsson, SR
p62/SQSTM1形成自噬降解的蛋白质聚集体，并对亨廷顿蛋白诱导的细胞死亡具有保护作用。
影响因子：
7.8
作者：
Bjorkoy, Geir;Lamark, Trond;Brech, Andreas;Outzen, Heidi;Perander, Maria;Overvatn, Aud;Stenmark, Harald;Johansen, Terje
通讯作者：
Johansen, Terje
影响因子：
14.8
作者：
Gonzalgo, Mark L.;Liang, Gangning
通讯作者：
Liang, Gangning
影响因子：
11.2
作者：
Fehrenbacher, Nicole;Bastholm, Lone;Jaattela, Marja
通讯作者：
Jaattela, Marja
溶酶体膜通透性以线粒体依赖性方式诱导细胞死亡。
DOI：
10.1084/jem.20021952
发表时间：
2003-05-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Boya P;Andreau K;Poncet D;Zamzami N;Perfettini JL;Metivier D;Ojcius DM;Jäättelä M;Kroemer G
通讯作者：
Kroemer G