Lefebvre Bruno, Brand Céline, Flajollet Sébastien, Lefebvre Philippe
Institut National de la Santé et de la Recherche Médicale, Unité 545, Faculté de Médecine Henri Warembourg, 1 Place de Verdun, 59045 Lille cedex, France.
Mol Endocrinol. 2006 Sep;20(9):2109-21. doi: 10.1210/me.2005-0321. Epub 2006 Apr 13.
The retinoic acid receptor beta2 (RARbeta2) is a potent, retinoid-inducible tumor suppressor gene, which is a critical molecular relay for retinoid actions in cells. Its down-regulation, or loss of expression, leads to resistance of cancer cells to retinoid treatment. Up to now, no primary mechanism underlying the repression of the RARbeta2 gene expression, hence affecting cellular retinoid sensitivity, has been identified. Here, we demonstrate that the phosphoinositide 3-kinase/Akt signaling pathway affects cellular retinoid sensitivity, by regulating corepressor recruitment to the RARbeta2 promoter. Through direct phosphorylation of the corepressor silencing mediator for retinoic and thyroid hormone receptors (SMRT), Akt stabilized RAR/SMRT interaction, leading to an increased tethering of SMRT to the RARbeta2 promoter, decreased histone acetylation, down-regulation of the RARbeta2 expression, and impaired cellular differentiation in response to retinoid. The phosphoinositide 3-kinase/Akt signaling pathway, an important modulator of cellular survival, has thus a direct impact on cellular retinoid sensitivity, and its deregulation may be the triggering event in retinoid resistance of cancer cells.
维甲酸受体β2（RARβ2）是一种强效的、类维生素A诱导的肿瘤抑制基因，它是细胞中类维生素A作用的关键分子传导途径。其下调或表达缺失会导致癌细胞对类维生素A治疗产生抗性。到目前为止，尚未确定RARβ2基因表达受抑制从而影响细胞类维生素A敏感性的主要机制。在此，我们证明磷酸肌醇3激酶/Akt信号通路通过调节共抑制因子与RARβ2启动子的结合来影响细胞类维生素A敏感性。通过对维甲酸和甲状腺激素受体沉默介质（SMRT）这种共抑制因子的直接磷酸化，Akt稳定了RAR/SMRT相互作用，导致SMRT与RARβ2启动子的结合增加、组蛋白乙酰化减少、RARβ2表达下调以及对类维生素A的细胞分化受损。磷酸肌醇3激酶/Akt信号通路作为细胞存活的重要调节因子，因此对细胞类维生素A敏感性有直接影响，其失调可能是癌细胞类维生素A抗性的触发事件。
