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Down-regulation of the tumor suppressor gene RAR{beta}2 through the PI3K/Akt signaling pathway.

Abstract : The retinoic acid receptor (RAR) beta 2 (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 PI3K/Akt signaling pathway affects cellular retinoid sensitivity, by regulating corepressor recruitment to the RARbeta2 promoter. Through direct phosphorylation of the corepressor 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 PI3K/Akt signaling pathway, an important modulator of cellular survival, has thus a direct impact on cellular retinoid sensitivity and its deregulation may be the trigerring event in retinoid resistance of cancer cells.
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Contributor : Philippe Lefebvre Connect in order to contact the contributor
Submitted on : Monday, June 12, 2006 - 11:35:20 AM
Last modification on : Thursday, February 21, 2019 - 9:56:02 AM

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Bruno Lefebvre, Céline Brand, Sébastien Flajollet, Philippe Lefebvre. Down-regulation of the tumor suppressor gene RAR{beta}2 through the PI3K/Akt signaling pathway.. Mol Endocrinol, 2006, 20 (9), pp.2109-21. ⟨10.1210/me.2005-0321⟩. ⟨inserm-00079317⟩



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