Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
Cell Signal. 2013 Jan;25(1):19-25. doi: 10.1016/j.cellsig.2012.09.002. Epub 2012 Sep 7.
All-trans retinoic acid (atRA), one of the active ingredients of vitamin A, exerts canonical activities to regulate gene expression mediated by nuclear RA receptors (RARs). AtRA could also elicit certain non-canonical activities including, mostly, rapid activation of extracellular signal regulated kinase 1/2 (ERK1/2); but the mechanism was unclear. In this study, we have found that cellular retinoic acid binding protein I (CRABPI) mediates the non-canonical, RAR- and membrane signal-independent activation of ERK1/2 by atRA in various cellular backgrounds. In the context of embryonic stem cells (ESCs), atRA/CRABPI-dependent ERK1/2 activation rapidly affects ESC cell cycle, specifically to expand the G1 phase. This is mediated by ERK stimulation resulting in dephosphorylation of nuclear p27, which elevates nuclear p27 protein levels to block G1 progression to S phase. This is the first study to identify CRABPI as the mediator for non-canonical activation of ERK1/2 by atRA, and demonstrate a new functional role for CRABPI in modulating ESC cell cycle progression.
全反式视黄酸（atRA）是维生素 A 的一种活性成分，它通过核视黄酸受体（RARs）介导的基因表达发挥经典作用。atRA 还可以引起某些非经典作用，包括主要是细胞外信号调节激酶 1/2（ERK1/2）的快速激活；但机制尚不清楚。在这项研究中，我们发现细胞视黄酸结合蛋白 I（CRABPI）介导了 atRA 在各种细胞背景下通过 RAR 和膜信号非依赖性激活 ERK1/2 的非经典作用。在胚胎干细胞（ESCs）的背景下，atRA/CRABPI 依赖性 ERK1/2 激活迅速影响 ESC 细胞周期，特别是扩大 G1 期。这是通过 ERK 刺激介导的，导致核 p27 的去磷酸化，从而提高核 p27 蛋白水平以阻止 G1 期向 S 期的进展。这是第一项确定 CRABPI 作为 atRA 非经典激活 ERK1/2 的介质的研究，并证明了 CRABPI 在调节 ESC 细胞周期进展中的新功能作用。
