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首页> 外文期刊>Molecular and Cellular Biology >Protein Kinase Cδ Regulates Keratinocyte Death and Survival by Regulating Activity and Subcellular Localization of a p38δ-Extracellular Signal-Regulated Kinase 1/2 Complex
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Protein Kinase Cδ Regulates Keratinocyte Death and Survival by Regulating Activity and Subcellular Localization of a p38δ-Extracellular Signal-Regulated Kinase 1/2 Complex

机译：蛋白激酶Cδ通过调节p38δ-细胞外信号调节激酶1/2复合物的活性和亚细胞定位来调节角质形成细胞的死亡和存活。

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Protein kinase Cδ (PKCδ) is an important regulator of apoptosis in epidermal keratinocytes. However, little information is available regarding the downstream kinases that mediate PKCδ-dependent keratinocyte death. This study implicates p38δ mitogen-activated protein kinase (MAPK) as a downstream carrier of the PKCδ-dependent death signal. We show that coexpression of PKCδ with p38δ produces profound apoptosis-like morphological changes. These morphological changes are associated with increased sub-G1 cell population, cytochrome c release, loss of mitochondrial membrane potential, caspase activation, and PARP cleavage. This death response is specific for the combination of PKCδ and p38δ and is not produced by replacing PKCδ with PKCα or p38δ with p38α. A constitutively active form of MEK6, an upstream activator of p38δ, can also produce cell death when coupled with p38δ. In addition, concurrent p38δ activation and extracellular signal-regulated kinase 1/2 (ERK1/2) inactivation are required for apoptosis. Regarding this inverse regulation, we describe a p38δ-ERK1/2 complex that may coordinate these changes in activity. We further show that this p38δ-ERK1/2 complex relocates into the nucleus in response to PKCδ expression. This regulation appears to be physiological, since H2O2, a known inducer of keratinocyte apoptosis, promotes identical PKCδ and p38δ-ERK1/2 activity changes, leading to similar morphological changes.
机译：蛋白激酶Cδ（PKCδ）是表皮角质形成细胞凋亡的重要调节剂。然而，关于下游激酶介导PKCδ依赖性角质形成细胞死亡的信息很少。这项研究暗示p38δ丝裂原活化蛋白激酶（MAPK）作为PKCδ依赖性死亡信号的下游载体。我们显示PKCδ与p38δ的共表达产生深刻的凋亡样形态变化。这些形态学改变与sub-G 1 细胞数量增加，细胞色素 c 释放，线粒体膜电位丧失，胱天蛋白酶激活和PARP裂解有关。该死亡反应对于PKCδ和p38δ的组合是特异性的，并且不是通过用PKCα代替PKCδ或用p38α代替p38δ而产生的。当与p38δ结合时，MEK6的组成型活性形式（p38δ的上游激活剂）也可导致细胞死亡。此外，细胞凋亡需要同时发生p38δ激活和细胞外信号调节激酶1/2（ERK1 / 2）失活。关于这种逆向调控，我们描述了一个p38δ-ERK1/ 2复合物，它可以协调这些活性的变化。我们进一步表明，该p38δ-ERK1/ 2复合物响应PKCδ表达而重新定位到细胞核中。这种调节似乎是生理性的，因为已知的角质形成细胞凋亡诱导剂H 2 O 2 促进相同的PKCδ和p38δ-ERK1/ 2活性变化，从而导致相似的形态变化。

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