Subcellular localization of PUMA regulates its pro-apoptotic activity in Burkitt's lymphoma B cells.
Subcellular localization of PUMA regulates its pro-apoptotic activity in Burkitt's lymphoma B cells.
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DOI：
10.18632/oncotarget.5901
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发表时间：
2015-11-10
期刊：
影响因子：
--
通讯作者：
Vazquez A
中科院分区：
文献类型：
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作者：
Ambroise G;Portier A;Roders N;Arnoult D;Vazquez A
仅 BH3 蛋白 PUMA（p53 上调细胞凋亡调节剂）是细胞凋亡的主要调节剂。它属于 Bcl-2 蛋白家族，负责通过控制内在（线粒体）凋亡途径来维持线粒体外膜的完整性。我们在此描述了一种通过控制 PUMA 亚细胞分布来调节 PUMA 激活的新途径。令人惊讶的是，正常活化的人 B 淋巴细胞中 PUMA 的上调和伯基特淋巴瘤 (BL) 中 PUMA 的高水平均与细胞死亡无关。我们发现 PUMA 定位于这些细胞的细胞质中。相比之下，发现各种凋亡触发信号可促进 PUMA 易位到这些细胞中的线粒体，导致细胞凋亡。这种细胞凋亡与线粒体 PUMA 与 Bcl-2 家族的抗细胞凋亡成员（例如 Bcl-2 和 Mcl-1）的结合有关。这种易位不依赖于半胱天冬酶，但可以通过抑制或敲低 MAPK 激酶 p38 的表达来阻止。我们的数据表明，PUMA 在细胞质中的积累可能对于该蛋白无需事先转录而参与细胞凋亡很重要。该调节途径可能是分化和致瘤过程的重要特征。
The BH3-only protein PUMA (p53-upregulated modulator of apoptosis) is a major regulator of apoptosis. It belongs to the Bcl-2 family of proteins responsible for maintaining mitochondrial outer membrane integrity by controlling the intrinsic (mitochondrial) apoptotic pathway. We describe here a new pathway regulating PUMA activation through the control of its subcellular distribution. Surprisingly, neither PUMA upregulation in normal activated human B lymphocytes nor high levels of PUMA in Burkitt's lymphoma (BL) were associated with cell death. We show that PUMA is localized to the cytosol in these cells. By contrast, various apoptosis-triggering signals were found to promote the translocation of PUMA to the mitochondria in these cells, leading to their death by apoptosis. This apoptosis was associated with the binding of mitochondrial PUMA to anti-apoptotic members of the Bcl-2 family, such as Bcl-2 and Mcl-1. This translocation was caspase-independent but was prevented by inhibiting or knocking down the expression of the MAPK kinase p38. Our data suggest that the accumulation of PUMA in the cytosol may be important for the participation of this protein in apoptosis without the need for prior transcription. This regulatory pathway may be an important feature of differentiation and tumorigenic processes.