Goodwin Research Laboratory, Department of Biochemistry and Molecular Biology, The Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.
Cell Death Differ. 2013 Apr;20(4):558-66. doi: 10.1038/cdd.2012.153. Epub 2012 Dec 14.
The current paradigm states that the Akt signaling pathway phosphorylates the human oncoprotein mouse double minute 2 (MDM2), leading to its nuclear translocation and degradation of the tumor suppressor p53. Here we report a novel Akt signaling pathway elicited by MDM2. Upregulation of endogenous MDM2 promotes, whereas its downregulation diminishes, Akt phosphorylation irrespective of p53 status. MDM2 requires phosphatidylinositol (PI)3-kinase activity for enhancing Akt phosphorylation and upregulates this activity by repressing transcription of the regulatory subunit p85 of PI3-kinase. MDM2 interacts with the repressor element-1 silencing transcription factor (REST), a tumor suppressor that functions by downregulating PI3-kinase activity and Akt phosphorylation, prevents localization of REST on the p85 promoter and represses p85 expression. The deletion mutant of MDM2 capable of upregulating Akt phosphorylation represses p85 expression and interferes with localization of REST on the p85 promoter, whereas the deletion mutant of MDM2 that does not increase Akt phosphorylation cannot perform these functions. Silencing of REST abrogates the ability of MDM2 to upregulate Akt phosphorylation and downregulate p85 expression, implicating the ability of MDM2 to interact with REST in its ability to inhibit p85 expression and activate Akt phosphorylation. Inhibition of MDM2-mediated Akt phosphorylation with an Akt-phosphorylation-specific inhibitor abrogates its ability to improve cell survival. Consistently, the Akt phosphorylation function of MDM2 was required for its ability to improve cell survival after treatment with a chemotherapeutic drug. Our report not only unravels a novel signaling pathway that contributes to cell survival but also implicates a p53-independent transcription regulatory function of MDM2 in Akt signaling.
当前的模式表明，Akt 信号通路使人类癌蛋白小鼠双微体 2（MDM2）磷酸化，导致其核易位和肿瘤抑制因子 p53 的降解。在这里，我们报告了一种由 MDM2 引发的新型 Akt 信号通路。内源性 MDM2 的上调促进了 Akt 的磷酸化，而下调则减少了 Akt 的磷酸化，而不管 p53 状态如何。MDM2 需要磷脂酰肌醇（PI）3-激酶活性来增强 Akt 的磷酸化，并通过抑制 PI3-激酶调节亚基 p85 的转录来上调这种活性。MDM2 与抑制元件-1 沉默转录因子（REST）相互作用，REST 是一种肿瘤抑制因子，通过下调 PI3-激酶活性和 Akt 的磷酸化来发挥作用，防止 REST 在 p85 启动子上的定位并抑制 p85 的表达。能够上调 Akt 磷酸化的 MDM2 缺失突变体抑制 p85 的表达并干扰 REST 在 p85 启动子上的定位，而不能增加 Akt 磷酸化的 MDM2 缺失突变体不能执行这些功能。沉默 REST 可消除 MDM2 上调 Akt 磷酸化和下调 p85 表达的能力，表明 MDM2 与 REST 相互作用的能力与其抑制 p85 表达和激活 Akt 磷酸化的能力有关。用 Akt 磷酸化特异性抑制剂抑制 MDM2 介导的 Akt 磷酸化可消除其改善细胞存活的能力。一致地，MDM2 改善细胞存活的 Akt 磷酸化功能对于其在化疗药物治疗后改善细胞存活的能力是必需的。我们的报告不仅揭示了促进细胞存活的新信号通路，而且还暗示了 MDM2 在 Akt 信号中的一种与 p53 无关的转录调节功能。
