Inhibition of protein phosphatase-1 is linked to phosphorylation of p53 and apoptosis.
Inhibition of protein phosphatase-1 is linked to phosphorylation of p53 and apoptosis.
复制标题
蛋白磷酸酶 1 的抑制与 p53 磷酸化和细胞凋亡有关。
DOI：
10.1023/a:1013508811252
复制
发表时间：
2002
期刊：
影响因子：
--
通讯作者：
Rogers,TB
中科院分区：
文献类型：
--
作者：
Long,X;Wu,G;Gaa,ST;Rogers,TB
p53是一种多功能蛋白，其活性可通过磷酸化和去磷酸化来调节。在这项研究中，我们试图研究的概念，丝氨酸/苏氨酸磷酸酶（PP-1和PP-2A）是p53依赖性凋亡途径的活性调节剂。新生大鼠心肌细胞暴露于已建立的凋亡剂，巴弗洛霉素A1（BAF）或星形孢菌素（STAU）诱导凋亡，并导致PP-1活性降低35%。这种反应仅限于细胞凋亡刺激，因为苯乙哌啶治疗既不降低PP-1和PP-2A活性，也不诱导心肌细胞DNA片段化。磷酸化p53的水平作为BAF或STAU处理的结果而增加。我们通过使用磷酸酶抑制剂冈田酸和反义策略进一步研究了PP-1抑制对心肌细胞的影响。冈田酸（100 nM）导致PP-1活性降低45%，增强p53磷酸化，并刺激细胞凋亡。此外，过表达的反义PP-1催化亚基转录导致PP-1的表达下降44%，而PP-2A催化亚基的水平没有变化，也诱发DNA片段化。我们的数据支持这样的观点，即PP-1活性降低是凋亡过程中的重要信号事件。
p53 is a multifunctional protein and its activity can be modulated by phosphorylation and dephosphorylation. In this study, we sought to examine the notion that serine/threonine phosphatases (PP-1 and PP-2A) are active modulators of the p53-dependent apoptotic pathway. Exposure of neonatal rat cardiomyocytes to the established apoptotic agents, bafilomycin A1 (BAF) or staurosporine (STAU) induced apoptosis and caused a decrease in PP-1 activity of 35%. This response was restricted to apoptotic stimuli as treatment with phenylephrine neither decreased PP-1 and PP-2A activity nor induced DNA fragmentation in cardiomyocytes. The level of phosphorylated p53 was increased as a result of BAF or STAU-treatment. We further examined the effect of PP-1 inhibition on cardiomyocytes by the use of the phosphatase inhibitor, okadaic acid, and an antisense strategy. Okadaic acid (100 nM) resulted in a decrease in PP-1 activity of 45%, enhanced phosphorylation of p53, and stimulated apoptosis. Furthermore, overexpression of the antisense PP-1 catalytic subunit transcript caused a 44% decrease in expression of PP-1, with no change in the levels of the PP-2A catalytic subunit, and also evoked DNA fragmentation. Our data support the view that decreased activity of PP-1 is an important signaling event in the apoptotic process.