ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation
ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation
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DOI：
10.1038/ncb1676
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发表时间：
2008-02-01
影响因子：
21.3
通讯作者：
Hung, Mien-Chie
中科院分区：
文献类型：
--
作者：
Yang, Jer-Yen;Zong, Cong S.;Hung, Mien-Chie
已知RAS-ERK通路在分化、增殖和肿瘤进展中起关键作用。在这里，我们发现ERK通过直接与FOXO3a的Ser 294、Ser 344和Ser 425相互作用并磷酸化FOXO3a，从而下调叉头盒O3a (FOXO3a)，从而促进细胞增殖和肿瘤发生。erk磷酸化的FOXO3a通过mdm2介导的泛素-蛋白酶体途径降解。然而，非磷酸化的FOXO3a突变体对小鼠双分钟2 （MDM2）的相互作用和降解具有抗性，从而对细胞增殖和致瘤性有很强的抑制作用。综上所述，我们的研究阐明了RAS-ERK和MDM2负调控FOXO3a在细胞生长和肿瘤发生中的新途径。
The RAS-ERK pathway is known to play a pivotal role in differentiation, proliferation and tumour progression. Here, we show that ERK downregulates Forkhead box O 3a (FOXO3a) by directly interacting with and phosphorylating FOXO3a at Ser 294, Ser 344 and Ser 425, which consequently promotes cell proliferation and tumorigenesis. The ERK-phosphorylated FOXO3a degrades via an MDM2-mediated ubiquitin-proteasome pathway. However, the non-phosphorylated FOXO3a mutant is resistant to the interaction and degradation by murine double minute 2 (MDM2), thereby resulting in a strong inhibition of cell proliferation and tumorigenicity. Taken together, our study elucidates a novel pathway in cell growth and tumorigenesis through negative regulation of FOXO3a by RAS-ERK and MDM2.