WIPI-dependent autophagy during neutrophil differentiation of NB4 acute promyelocytic leukemia cells.
WIPI-dependent autophagy during neutrophil differentiation of NB4 acute promyelocytic leukemia cells.
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DOI：
10.1038/cddis.2014.261
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发表时间：
2014-07-03
影响因子：
9
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中科院分区：
文献类型：
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与磷酸肌醇 (WIPI) 家族相互作用的 WD 重复蛋白成员是磷脂酰肌醇 3-磷酸 (PI3P) 效应子，它们对于自噬体的形成至关重要。自噬体是一种独特的双膜细胞器，是自噬的特征，自噬是一种具有细胞保护和稳态功能的大量降解机制。 WIPI-1 和 WIPI-2 在几种实体瘤中异常表达，将这些基因与癌发生联系起来。我们现在发现，在 98 名原发性急性髓系白血病 (AML) 患者样本（复杂核型；t(8;21)；t(15,17)；inv(16)）的大型队列中，WIPI-1 的表达显着降低。相比之下，WIPI-2 的表达仅在急性早幼粒细胞白血病 (APL)（AML 的一种独特亚型）中降低 (t(15,17))。由于 AML 细胞的分化受阻，我们测试了在全反式视黄酸 (ATRA) 诱导的 APL 中性粒细胞分化过程中 WIPI-1 和 WIPI-2 的表达水平是否增加。根据与未成熟母细胞相比，粒细胞中WIPI-1的表达较高，在NB4 APL细胞的中性粒细胞分化过程中，WIPI-1而非WIPI-2的表达被显着诱导。有趣的是，WIPI-1 表达的诱导依赖于转录因子 PU.1（骨髓细胞生成的主要调节因子），这支持了我们的观点，即缺乏适当 PU-1 活性的 AML 患者中 WIPI-1 表达降低。此外，敲除 NB4 细胞中的 WIPI-1 显着减弱自噬通量并显着减少中性粒细胞分化。这一结果也是通过敲低 WIPI-2 实现的，表明 WIPI-1 和 WIPI-2 在 NB4 细胞自噬开始时介导 PI3P 信号方面都是功能所需的，而不是多余的。与这些数据一致，在 WIPI 上游产生 PI3P 的 PI3KC3 (hVPS34) 的下调也抑制中性粒细胞分化。总之，我们证明 WIPI-1 和 WIPI-2 都是中性粒细胞分化过程中 PI3P 依赖性自噬活性所必需的，并且 PU.1 依赖性 WIPI-1 表达在原发性 AML 患者样本中显着受到抑制，并且自噬流的诱导与 APL 细胞的中性粒细胞分化相关。
Members of the WD-repeat protein interacting with phosphoinositides (WIPI) family are phosphatidylinositol 3-phosphate (PI3P) effectors that are essential for the formation of autophagosomes. Autophagosomes, unique double-membraned organelles, are characteristic for autophagy, a bulk degradation mechanism with cytoprotective and homeostatic function. Both, WIPI-1 and WIPI-2 are aberrantly expressed in several solid tumors, linking these genes to carcinogenesis. We now found that the expression of WIPI-1 was significantly reduced in a large cohort of 98 primary acute myeloid leukemia (AML) patient samples (complex karyotypes; t(8;21); t(15,17); inv(16)). In contrast, the expression of WIPI-2 was only reduced in acute promyelocytic leukemia (APL), a distinct subtype of AML (t(15,17)). As AML cells are blocked in their differentiation, we tested if the expression levels of WIPI-1 and WIPI-2 increase during all-trans retinoic acid (ATRA)-induced neutrophil differentiation of APL. According to the higher WIPI-1 expression in granulocytes compared with immature blast cells, WIPI-1 but not WIPI-2 expression was significantly induced during neutrophil differentiation of NB4 APL cells. Interestingly, the induction of WIPI-1 expression was dependent on the transcription factor PU.1, a master regulator of myelopoiesis, supporting our notion that WIPI-1 expression is reduced in AML patients lacking proper PU-1 activity. Further, knocking down WIPI-1 in NB4 cells markedly attenuated the autophagic flux and significantly reduced neutrophil differentiation. This result was also achieved by knocking down WIPI-2, suggesting that both WIPI-1 and WIPI-2 are functionally required and not redundant in mediating the PI3P signal at the onset of autophagy in NB4 cells. In line with these data, downregulation of PI3KC3 (hVPS34), which generates PI3P upstream of WIPIs, also inhibited neutrophil differentiation. In conclusion, we demonstrate that both WIPI-1 and WIPI-2 are required for the PI3P-dependent autophagic activity during neutrophil differentiation, and that PU.1-dependent WIPI-1 expression is significantly repressed in primary AML patient samples and that the induction of autophagic flux is associated with neutrophil differentiation of APL cells.
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影响因子：
5.3
作者：
Kang, Yoon-A;Sanalkumar, Rajendran;Bresnick, Emery H.
通讯作者：
Bresnick, Emery H.
影响因子：
20.3
作者：
Federzoni, Elena A.;Valk, Peter J. M.;Tschan, Mario P.
通讯作者：
Tschan, Mario P.
DOI：
10.1016/j.bbrc.2013.07.056
发表时间：
2013-08-23
影响因子：
3.1
作者：
Brigger D;Torbett BE;Chen J;Fey MF;Tschan MP
通讯作者：
Tschan MP
影响因子：
11.4
作者：
Duprez, E;Benoit, G;Lanotte, M
通讯作者：
Lanotte, M
影响因子：
11.8
作者：
Lu, Qun;Yang, Peiguo;Zhang, Hong
通讯作者：
Zhang, Hong