Kanungo Jyotshna
Division of Neurotoxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079. United States.
Anticancer Agents Med Chem. 2017;17(9):1184-1198. doi: 10.2174/1871520616666160615065000.
Retinoic acid (RA), especially all-trans retinoic acid is the most potent natural metabolite of vitamin A. RA is involved in a variety of biological functions including embryogenesis, cell differentiation and apoptosis. RA acts through its nuclear receptors to induce transcription of specific target genes. Mouse P19 embryonic carcinoma (EC) stem cells (ES) are one of the most studied in vitro systems for RA-induced differentiation. P19 ES cells can differentiate to endodermal-like, mesodermal-like, and neuronal-like phenotypes in response to specific morphogens including RA and dimethyl sulfoxide (DMSO). At low concentrations, RA directs P19 ES cells to differentiate into cells displaying an endodermal phenotype, whereas at higher concentrations it induces differentiation to neuroectoderm. In the past, many RA---regulated genes have been discovered in EC and ES cells and efforts are ongoing to elucidate the exact mechanisms of RA-induced ES cell differentiation and apoptosis. In the RA-triggered differentiation process of the P19 ES cells, several proteins belonging to different families participate, some being obligatory while others, dispensable. Revealing the mechanisms behind RA-induced effects on ES cells has a bearing on understanding how cells proliferate, differentiate and undergo apoptosis that can provide greater insight into cancer biology and therapy. In addition to summarizing the reports on gene/protein targets of RA in stem cells, the signaling pathways driven by some of the specific class of proteins in the presence or absence of RA in P19 ES cell differentiation, especially to an endodermal phenotype, are the focus of this review.
视黄酸（RA），尤其是全反式视黄酸，是维生素A最有效的天然代谢产物。RA参与多种生物学功能，包括胚胎发育、细胞分化和凋亡。RA通过其核受体发挥作用，诱导特定靶基因的转录。小鼠P19胚胎癌（EC）干细胞（ES）是研究最多的RA诱导分化的体外系统之一。P19 ES细胞可响应包括RA和二甲基亚砜（DMSO）在内的特定形态发生素，分化为内胚层样、中胚层样和神经样表型。在低浓度下，RA引导P19 ES细胞分化为表现出内胚层表型的细胞，而在高浓度下，它诱导分化为神经外胚层。过去，在EC和ES细胞中发现了许多受RA调控的基因，目前正在努力阐明RA诱导ES细胞分化和凋亡的确切机制。在P19 ES细胞由RA触发的分化过程中，几个不同家族的蛋白质参与其中，有些是必需的，而有些则是可有可无的。揭示RA对ES细胞诱导作用背后的机制，有助于理解细胞如何增殖、分化和凋亡，从而为癌症生物学和治疗提供更深入的见解。除了总结关于干细胞中RA的基因/蛋白质靶点的报告外，本综述的重点是在P19 ES细胞分化过程中，尤其是向内胚层表型分化时，在有或没有RA的情况下，某些特定类别的蛋白质驱动的信号通路。
