RREB-1 Is a Transcriptional Repressor of HLA-G

Abstract The nonclassical HLA-G is a molecule specifically involved in immune tolerance with highly restricted tissue distribution in healthy conditions. Yet it is overexpressed in numerous tumors and in allografts with better acceptance. Major mechanisms involved in regulation of HLA-G transcription are still poorly described. Thus, to characterize these mechanisms we have developed a specific proteomic approach to identify proteins that bind differentially to the HLA-G gene promoter by promoter pull-down assay followed by spectrometry mass analysis. Among specific binding factors, we focused on RREB-1, a ras-responsive element binding protein 1. We demonstrated that RREB-1 represses HLA-G transcriptional activity and binds three ras response elements within the HLA-G promoter. RREB-1 protein, specifically in HLA-G-negative cells, interacts with subunits of CtBP complex implicated in chromatin remodeling. This demonstration is the first of a repressor factor of HLA-G transcriptional activity taking part in HLA-G repression by epigenetic mechanisms.</jats:p

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

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