Tsanov Kaloyan M, Pearson Daniel S, Wu Zhaoting, Han Areum, Triboulet Robinson, Seligson Marc T, Powers John T, Osborne Jihan K, Kane Susan, Gygi Steven P, Gregory Richard I, Daley George Q
Stem Cell Transplantation Program, Division of Hematology/Oncology, Manton Center for Orphan Disease Research, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Nat Cell Biol. 2017 Jan;19(1):60-67. doi: 10.1038/ncb3453. Epub 2016 Dec 19.
Signalling and post-transcriptional gene control are both critical for the regulation of pluripotency, yet how they are integrated to influence cell identity remains poorly understood. LIN28 (also known as LIN28A), a highly conserved RNA-binding protein, has emerged as a central post-transcriptional regulator of cell fate through blockade of let-7 microRNA biogenesis and direct modulation of mRNA translation. Here we show that LIN28 is phosphorylated by MAPK/ERK in pluripotent stem cells, which increases its levels via post-translational stabilization. LIN28 phosphorylation had little impact on let-7 but enhanced the effect of LIN28 on its direct mRNA targets, revealing a mechanism that uncouples LIN28's let-7-dependent and -independent activities. We have linked this mechanism to the induction of pluripotency by somatic cell reprogramming and the transition from naive to primed pluripotency. Collectively, our findings indicate that MAPK/ERK directly impacts LIN28, defining an axis that connects signalling, post-transcriptional gene control, and cell fate regulation.
信号传导和转录后基因调控对于多能性的调节都至关重要，然而它们如何整合以影响细胞特性仍知之甚少。LIN28（也称为LIN28A）是一种高度保守的RNA结合蛋白，已成为细胞命运的核心转录后调节因子，通过阻断let-7微小RNA的生物合成和直接调节mRNA翻译来实现。在这里，我们表明LIN28在多能干细胞中被MAPK/ERK磷酸化，通过翻译后稳定增加其水平。LIN28磷酸化对let-7影响不大，但增强了LIN28对其直接mRNA靶标的作用，揭示了一种解开LIN28的let-7依赖性和非依赖性活性的机制。我们已将此机制与体细胞重编程诱导多能性以及从幼稚多能性向始发态多能性的转变联系起来。总体而言，我们的研究结果表明MAPK/ERK直接影响LIN28，定义了一个连接信号传导、转录后基因调控和细胞命运调节的轴。
