Down-regulation of the tumor suppressor gene RAR{beta}2 through the PI3K/Akt signaling pathway. - Archive ouverte HAL Access content directly
Journal Articles Mol Endocrinol Year : 2006

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

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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.

Dates and versions

inserm-00079317 , version 1 (12-06-2006)

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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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