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Down-Regulation of the Tumor Suppressor Gene Retinoic Acid Receptor ß2 through the Phosphoinositide 3-Kinase/Akt Signaling Pathway

Institut National de la Santé et de la Recherche Médicale, Unité 459, and Université de Lille, Faculté de Médecine Henri Warembourg, F-59045 Lille, France

Address all correspondence and requests for reprints to: Dr. Bruno Lefebvre, 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. E-mail: bruno.lefebvre{at}lille.inserm.fr.

The retinoic acid receptor ß2 (RARß2) 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 RARß2 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 RARß2 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 RARß2 promoter, decreased histone acetylation, down-regulation of the RARß2 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.

NURSA Molecule Pages Link:

Nuclear Receptors:   RARβ

Coregulators:   NCOR  |  SMRT

Ligands:   all-trans-Retinoic acid

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