Depletion of kinesin 5B affects lysosomal distribution and stability and induces peri-nuclear accumulation of autophagosomes in cancer cells.
Depletion of kinesin 5B affects lysosomal distribution and stability and induces peri-nuclear accumulation of autophagosomes in cancer cells.
复制标题
DOI：
10.1371/journal.pone.0004424
复制
发表时间：
2009
期刊：
影响因子：
3.7
通讯作者：
Nylandsted J
中科院分区：
文献类型：
--
作者：
Cardoso CM;Groth-Pedersen L;Høyer-Hansen M;Kirkegaard T;Corcelle E;Andersen JS;Jäättelä M;Nylandsted J
溶酶体转运增强与转移性癌症有关。为了发现与癌症相关的溶酶体马达蛋白，我们比较了亲本乳腺癌细胞和高侵袭性表达ErbB2活性形式(ΔN-ErbB2)的MCF-7细胞的溶酶体蛋白质组。质谱学分析表明，KIF5B是MCF-7细胞中唯一与溶酶体结合的微管马达，异位ΔN-ErbB2增强了其与溶酶体的结合。亚细胞分离分析表明，KIF5B在HeLa宫颈癌细胞中也与溶酶体相关。KIF5B的缺失在HeLa细胞中引发了溶酶体的外周聚集，随后是溶酶体的失稳和细胞死亡。然而，在这些细胞中，溶酶体对质膜损伤的胞吐作用和液相内吞作用是正常的。HeLa和MCF-7细胞似乎表达相似水平的KIF5B亚型，但KIF5B缺失的MCF-7细胞的死亡表型较弱。令人惊讶的是，KIF5B的缺失抑制了雷帕霉素诱导的MCF-7细胞自噬小体的积累。在KIF5B缺失的细胞中，自噬小体在高尔基体附近形成和聚集，而在对照细胞中，自噬小体均匀分布在细胞质中。我们的数据确定KIF5B是一种与癌症相关的溶酶体马达蛋白，在自噬小体形成中具有额外的功能。
Enhanced lysosomal trafficking is associated with metastatic cancer. In an attempt to discover cancer relevant lysosomal motor proteins, we compared the lysosomal proteomes from parental MCF-7 breast cancer cells with those from highly invasive MCF-7 cells that express an active form of the ErbB2 (ΔN-ErbB2). Mass spectrometry analysis identified kinesin heavy chain protein KIF5B as the only microtubule motor associated with the lysosomes in MCF-7 cells, and ectopic ΔN-ErbB2 enhanced its lysosomal association. KIF5B associated with lysosomes also in HeLa cervix carcinoma cells as analyzed by subcellular fractionation. The depletion of KIF5B triggered peripheral aggregations of lysosomes followed by lysosomal destabilization, and cell death in HeLa cells. Lysosomal exocytosis in response to plasma membrane damage as well as fluid phase endocytosis functioned, however, normally in these cells. Both HeLa and MCF-7 cells appeared to express similar levels of the KIF5B isoform but the death phenotype was weaker in KIF5B-depleted MCF-7 cells. Surprisingly, KIF5B depletion inhibited the rapamycin-induced accumulation of autophagosomes in MCF-7 cells. In KIF5B-depleted cells the autophagosomes formed and accumulated in the close proximity to the Golgi apparatus, whereas in the control cells they appeared uniformly distributed in the cytoplasm. Our data identify KIF5B as a cancer relevant lysosomal motor protein with additional functions in autophagosome formation.
登录
查看更多内容
影响因子：
11.2
作者：
Fehrenbacher, N;Gyrd-Hansen, M;Jäättelä, M
通讯作者：
Jäättelä, M
影响因子：
13.3
作者：
Ostenfeld, Marie Stampe;Hoyer-Hansen, Maria;Jaattela, Maria
通讯作者：
Jaattela, Maria
影响因子：
4.3
作者：
Gocheva, Vasilena;Joyce, Johanna A.
通讯作者：
Joyce, Johanna A.
影响因子：
64.5
作者：
Reddy, A;Caler, EV;Andrews, NW
通讯作者：
Andrews, NW
DOI：
10.1083/jcb.131.4.1039
发表时间：
1995-11
期刊：
The Journal of cell biology
影响因子：
--
作者：
Nakata T;Hirokawa N
通讯作者：
Hirokawa N