PP2A:B56ε, a Substrate of Caspase-3, Regulates p53-dependent and p53-independent Apoptosis during Development
PP2A:B56ε, a Substrate of Caspase-3, Regulates p53-dependent and p53-independent Apoptosis during Development
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DOI：
10.1074/jbc.m110.169581
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发表时间：
2010-11-05
影响因子：
4.8
通讯作者：
Yang, Jing
中科院分区：
文献类型：
--
作者：
Jin, Zhigang;Wallace, Lindsay;Yang, Jing
蛋白磷酸酶2A(PP2A)是表达最丰富的丝氨酸/苏氨酸蛋白磷酸酶之一。大量证据表明，PP2A是一种肿瘤抑制因子，在调节细胞凋亡中发挥重要作用。PP2A是一种异源三聚体蛋白质复合体。它的底物特异性、定位和活性受PP2A调节亚基的调节。最近的一项研究表明，PP2A的B56家族调节亚基B56 epsilon(PPP2R5E)的单核苷酸多态性与人软组织肉瘤有关。这增加了B56 epsilon参与肿瘤发生并在调节细胞凋亡中发挥重要作用的可能性。然而，这一假设尚未得到实验检验。我们之前的研究表明，在早期胚胎模式形成过程中，B56 epsilon调控着许多发育信号通路。在此，我们报道了B56 epsilon在调节细胞凋亡中的新功能。我们提供了B56 epsilon同时具有抗和促凋亡功能的证据。B56 epsilon抑制神经发育过程中P53非依赖的细胞凋亡，但触发P53依赖的细胞凋亡。从机制上讲，B56 epsilon仅通过控制P53蛋白的稳定性来调控依赖于P53的细胞凋亡途径。除了其调节细胞凋亡的功能外，我们还发现B56 epsilon经历了蛋白水解性切割。B56 epsilon的切割是由caspase-3介导的，发生在进化上保守的N端“DKXD”基序的羧基一侧。这些结果表明，作为caspase-3底物的B56 epsilon是细胞凋亡的重要调节因子。到目前为止，我们已经确定了B56 epsilon的另一种翻译异构体和caspase切割产物。对B56 epsilon转录后调控的意义进行了讨论。
Protein phosphatase 2A (PP2A) is one of the most abundantly expressed serine/threonine protein phosphatases. A large body of evidence suggests that PP2A is a tumor suppressor and plays critical roles in regulating apoptosis. PP2A is a heterotrimeric protein complex. Its substrate specificity, localization, and activity are regulated by regulatory subunits of PP2A. A recent study has demonstrated that single nucleotide polymorphism in B56 epsilon (PPP2R5E), a B56 family regulatory subunit of PP2A, is associated with human soft tissue sarcoma. This raises the possibility that B56 epsilon is involved in tumorigenesis and plays important roles in regulating apoptosis. However, this hypothesis has not been tested experimentally. Our previous studies revealed that B56 epsilon regulates a number of developmental signaling pathways during early embryonic patterning. Here we report novel functions of B56 epsilon in regulating apoptosis. We provide evidence that B56 epsilon has both anti-and pro-apoptotic functions. B56 epsilon suppresses p53-independent apoptosis during neural development, but triggers p53-dependent apoptosis. Mechanistically, B56 epsilon regulates the p53-dependent apoptotic pathway solely through controlling the stability of p53 protein. In addition to its function in regulating apoptosis, we show that B56 epsilon undergoes proteolytic cleavage. The cleavage of B56 epsilon is mediated by caspase-3 and occurs on the carboxyl side of an evolutionarily conserved N-terminal "DKXD" motif. These results demonstrate that B56 epsilon, a substrate of caspase-3, is an essential regulator of apoptosis. So far, we have identified an alternative translation isoform and a caspase cleavage product of B56 epsilon. The significance of post-transcriptional regulation of B56 epsilon is discussed.