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Peptidyl-prolyl cis|[sol]|trans isomerase Pin1 is critical for the regulation of PKB|[sol]|Akt stability and activation phosphorylation

机译:肽基脯氨酰顺式[[sol] |反式异构酶Pin1]对调节PKB | [sol] | Akt稳定性和激活磷酸化至关重要

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The serine/threonine protein kinase B (PKB, also known as Akt) plays a pivotal role in diverse cellular functions. Elevated expression of activated Akt has been detected in a wide variety of human cancers; however, the mechanism of Akt protein stability regulation remains unclear. In this study, we showed a strong correlation between the expression levels of an oncogenic peptidyl-prolyl cis/trans isomerase Pin1 and levels of Akt phosphorylation at S473 in multiple cancer types (PP=0.0052). We further showed that Pin1 regulated Akt stability and phosphorylation on S473 through the phosphorylated Thr-Pro motifs of Akt. These motifs are conserved evolutionary and are required for the maintenance of Akt stability and its interaction with Pin1. In addition, repressing Pin1 expression through either homologue Pin1 knockout or small interfering RNA-mediated knockingdown compromised its ability to protect Akt from degradation. Our results show how Akt protein stability is regulated by the peptidyl-prolyl cis/trans isomerase Pin1 and highlight the importance of this oncogenic network in human disease pathogenesis.
机译:丝氨酸/苏氨酸蛋白激酶B(PKB,也称为Akt)在多种细胞功能中起关键作用。已在多种人类癌症中检测到活化的Akt的表达升高;然而,Akt蛋白稳定性调节的机制仍不清楚。在这项研究中,我们显示了在多种癌症类型中,致癌肽基脯氨酰顺式/反式异构酶Pin1的表达水平与S473处Akt磷酸化水平之间有很强的相关性(PP = 0.0052)。我们进一步表明,Pin1通过Akt的磷酸化Thr-Pro基序调节S473上的Akt稳定性和磷酸化。这些基序是保守进化的,是维持Akt稳定性及其与Pin1相互作用所必需的。另外,通过同源Pin1敲除或小的干扰RNA介导的敲低来抑制Pin1表达会损害其保护Akt免于降解的能力。我们的结果表明,Akt蛋白的稳定性如何受肽基-脯氨酰顺/反异构酶Pin1调控,并突出了这种致癌网络在人类疾病发病机理中的重要性。

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