Protein kinase Cδ and apoptosis
Protein kinase Cδ and apoptosis
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DOI：
10.1042/bst0351001
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发表时间：
2007-11-01
影响因子：
3.9
通讯作者：
Reyland, M. E.
中科院分区：
文献类型：
--
作者：
Reyland, M. E.
PKC（蛋白激酶C）家族调节多种细胞功能，特定的同种异构体已被证明是细胞增殖和存活的关键调节因子。特别是，PKC δ在许多细胞类型中是一个关键的促凋亡信号。我们实验室的工作重点是了解PKC δ调节细胞凋亡的分子机制，以及这种普遍存在的激酶的促凋亡活性如何被调节，从而使细胞仅在适当的时候激活凋亡级联反应。我们已经确定了多个调控步骤，激活PKC三角洲的促凋亡功能，以响应基因毒素。我们的研究表明，凋亡信号诱导了调控区域PKC δ的快速翻译后修饰，从而促进了激酶从细胞质到细胞核的易位。在这些条件下，活性caspase 3也会在细胞核中积累，导致PKC δ的caspase裂解，并产生组成型活化的PKC δ [PKC δ催化片段]。与PUS不同的是，δ CF组成性地存在于细胞核中，PKC δ的核积累对细胞凋亡至关重要。因此，我们的研究表明，细胞核输入和PKC δ的严格调控对细胞存活至关重要，细胞核中PKC δ的caspase切割标志着细胞凋亡的不可逆承诺。
The PKC (protein kinase C) family regulates diverse cellular functions and specific isciforms have been shown to be critical regulators of cell proliferation and survival. in particular, PKC delta is known to be a critical pro-apoptotic signal in many cell types. Work in our laboratory has focused on understanding the molecular mechanisms through which PKC delta regulates apoptosis and on how the pro-apoptotic activity of this ubiquitous kinase, is regulated such that cells only activate the apoptotic cascade when appropriate. We have identified multiple regulatory steps that activate the pro-apoptotic function of PKC delta in response to genotoxins. Our studies show that apoptotic signals induce rapid post-translational modification of PKC delta in the regulatory domain, which facilitates translocation of the kinase from the cytoplasm to the nucleus. Active caspase 3 also accumulates in the nucleus under these conditions, resulting in caspase cleavage of PKC delta and generation of a constitutively activated form of PKC delta [delta CF (PKC delta catalytic fragment)]. in contrast with PUS, delta CF is constitutively present in the nucleus, and this nuclear accumulation of PKC delta is essential for apoptosis. Thus our studies suggest that tight regulation of nuclear import and of PKC delta is critical for cell survival and that caspase cleavage of PKC delta in the nucleus signals an irreversible commitment to apoptosis.