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首页> 外文期刊>Biochemistry >An Endogenous Electrophile that Modulates the Regulatory Mechanism of Protein Turnover:Inhibitory Effects of 15-Deoxy-DELTA~(12,14)-prostaglandin J_2 on Proteasome
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An Endogenous Electrophile that Modulates the Regulatory Mechanism of Protein Turnover:Inhibitory Effects of 15-Deoxy-DELTA~(12,14)-prostaglandin J_2 on Proteasome

机译：内源性亲电调节蛋白周转的调节机制：15-脱氧三角洲〜（12,14）-前列腺素J_2对蛋白酶体的抑制作用。

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摘要

Prostaglandin D_2 (PGD_2),a major cyclooxygenase product in a variety of tissues and cells,readily undergoes dehydration to yield electrophilic PGs,such as 15-deoxy-DELTA~(12,14)-PGJ_2 (15d-PGJ_2).We have previously shown that 15d-PGJ_2 potently induces apoptosis of SH-SY5Y human neuroblastoma cells via accumulation of the tumor suppressor gene product p53.In the study presented here,we investigated the molecular mechanisms involved in the 15d-PGJ_2-induced accumulation of p53.In was observed that 15d-PGJ_2 potently induces p53 protein experession but scarcely induced p53 gene expression.In addition,exposure of the cells to 15d-PGJ_2 resulted in an accumulation of ubiquitinated proteins and in a significant inhibition of proteasome activatives,suggesting that 15d-PGJ_2 acted on the ubiquitin-proteasome pathway,a regulatory mechanism of p53 turnover.The effects of 15d-PGJ_2 on the protein turnover were attributed to its electrophilic features,based on the observations that (i) the reduction of the double bond in the cyclopentenone ring of 15d-PGJ_2 virtually abolished the effects on protein turnover,(ii) overexpression of an endogenous redox regulator,thioredoxin 1,significantly retarded the inhibition of proteasome activities and accumulations of p53 and ubiquitinated proteins induced by 15d-PGJ_2,and (iii) treatment of SH-SY5Y cells with biotinylated 15d-PGJ_2 indeed resulted in the formation of a 15d-PGJ_2-proteasome conjugate.These data suggest that the modulation of proteasome activity may be involved in the mechanism responsible for the accumulation of p53 and subsequent induction of apoptotic cell death induced by 15d-PGJ_2.
机译：前列腺素D_2（PGD_2）是多种组织和细胞中的主要环加氧酶产物，容易脱水以生成亲电性PG，例如15-deoxy-DELTA〜（12,14）-PGJ_2（15d-PGJ_2）。结果表明，15d-PGJ_2通过抑癌基因产物p53的积累有效诱导SH-SY5Y人神经母细胞瘤细胞凋亡。在本研究中，我们研究了15d-PGJ_2诱导p53积累的分子机制。观察到15d-PGJ_2可以有效诱导p53蛋白表达，而几乎不诱导p53基因表达。此外，将细胞暴露于15d-PGJ_2会导致泛素化蛋白的积累并显着抑制蛋白酶体活化剂，提示15d-PGJ_2发挥了作用。 15d-PGJ_2对蛋白质更新的影响归因于其亲电子特性，这是基于以下观察结果：（i）还原15d-PGJ_2的环戊烯酮环中的双键几乎消除了对蛋白质更新的影响，（ii）内源性氧化还原调节剂硫氧还蛋白1的过表达显着延迟了蛋白酶体活性的抑制以及p53和泛素化蛋白的积累15d-PGJ_2，以及（iii）用生物素化的15d-PGJ_2处理SH-SY5Y细胞确实导致形成15d-PGJ_2-蛋白酶体偶联物。这些数据表明，蛋白酶体活性的调节可能参与了造成这种现象的机制15d-PGJ_2诱导p53的积累并诱导凋亡细胞死亡。

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