Selenium has been associated with an anti-cancer effect via the modulation of Akt. In order to investigate whether selenium modulates Akt by hitherto unidentified molecular mechanisms, we examined the effect of selenium on the stability and activity of Akt. Selenium induced destabilization of Akt which is coupled to its own enzyme activation. Mutation of T308 and S473 of Akt to alanine as well as the inhibition or depletion of upstream kinases for Akt activation blocked Akt degradation. These features of Akt degradation are reminiscent of the 'activation-induced suicidal degradation' mechanism. PTEN was also required for Akt destabilization as Akt activation alone was unable to elicit Akt degradation in the absence of PTEN. Conversely, PTEN introduction in PTEN-null prostate cancer cells restored the ability to degrade Akt upon selenium treatment. Collectively, selenium seems to achieve ultimate negative regulation of Akt signaling by destabilizing the protein, and this regulation mechanism might provide a paradigm for the anti-cancer activity of selenium.

译文

硒通过调节Akt与抗癌作用有关。为了研究硒是否通过迄今尚未确定的分子机制调节Akt,我们研究了硒对Akt稳定性和活性的影响。硒诱导的Akt失稳与其自身的酶活化有关。 Akt的T308和S473突变为丙氨酸,以及Akt激活的上游激酶的抑制或耗竭阻止Akt降解。 Akt降解的这些特征使人联想到“活化诱导的自杀降解”机制。 Akt不稳定也需要PTEN,因为在没有PTEN的情况下,仅Akt激活不能引发Akt降解。相反,在无PTEN的前列腺癌细胞中引入PTEN恢复了硒处理后降解Akt的能力。总体而言,硒似乎通过使蛋白质不稳定来实现对Akt信号的最终负调控,并且这种调控机制可能为硒的抗癌活性提供范例。

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