The phosphorylation site located in the A region of retinoic X receptor α is required for the antiproliferative effect of retinoic acid (RA) and the activation of RA target genes in F9 cells
The phosphorylation site located in the A region of retinoic X receptor α is required for the antiproliferative effect of retinoic acid (RA) and the activation of RA target genes in F9 cells
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DOI：
10.1074/jbc.m203623200
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发表时间：
2002-08-09
影响因子：
4.8
通讯作者：
Rochette-Egly, C
中科院分区：
文献类型：
--
作者：
Bastien, J;Adam-Stitah, S;Rochette-Egly, C
小鼠 F9 胚胎癌细胞构成了一个完善的细胞自主模型系统，用于体外研究视黄酸 (RA) 信号传导。 RA 诱导单层生长的 F9 细胞分化为内胚层样细胞，并降低其增殖率。视黄酸 X 受体 α (RXRalpha) 基因的敲除会消除内胚层分化和几种内源 RA 反应基因的诱导。 RXRa 无效细胞对 RA 的抗增殖反应也严重受损。此处通过建立在 RXRalpha 无效背景下重新表达 RXRa 的细胞系（野生型或在磷酸化位点 (RXRalphaS22A) 突变），研究了位于 N 端 A 区域 (Ser(22)) 的 RXRa 磷酸化位点的作用。我们发现 Ser(22) 对于 RA 诱导的内胚层分化是可有可无的，但对于几个 IRA 反应基因的表达至关重要。 Ser(22) 对于 RA 的抗增殖作用也是不可或缺的，并且是 RA 诱导的 p21(CIP) 和 p27(KIP) CKI 蛋白下调所必需的，已知这些蛋白参与细胞周期进程的控制。
Mouse F9 embryocarcinoma cells constitute a well established cell autonomous model system for investigating retinoic acid (RA) signaling in vitro. RA induces the differentiation of F9 cells grown as monolayers into endodermal-like cells and decreases their rate of proliferation. Knock-out of the retinoic X receptor alpha (RXRalpha) gene abolishes endodermal differentiation and the induction of several endogenous RA-responsive genes. RXRa null cells are also drastically impaired in their antiproliferative response to RA. The role of the RXRa phosphorylation site located in the N-terminal A region (Ser(22)) has been investigated here by establishing cell lines re-expressing RXRa either wild type or mutated at the phosphorylation site (RXRalphaS22A) in a RXRalpha-null background. We show that Ser(22) is dispensable for RA-induced endodermal differentiation but is crucial for the expression of several IRA-responsive genes. Ser(22) is also indispensable for the antiproliferative effect of RA and necessary for the RA-induced down-regulation of p21(CIP) and p27(KIP) CKIs proteins that are known to be involved in the control of cell cycle progression.