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You are here: Home / Teams / Systems Biology of Decision Making - O. Gandrillon / Publications (not up to date) / Expression levels of estrogen receptor beta are modulated by components of the molecular clock.

Expression levels of estrogen receptor beta are modulated by components of the molecular clock.

Wen Cai, Juliette Rambaud, Michele Teboul, Ingrid Masse, Gerard Benoit, Jan-Ake Gustafsson, Franck Delaunay, Vincent Laudet, and Ingemar Pongratz (2008)

Mol Cell Biol, 28(2):784-93.

Circadian regulation of gene expression plays a major role in health and disease. The precise role of the circadian system remains to be clarified, but it is known that circadian proteins generate physiological rhythms in organisms by regulating clock-controlled target genes. The estrogen receptor beta (ERbeta) is, together with ERalpha, a member of the nuclear receptor superfamily and a key mediator ofestrogen action. Interestingly, recent studies show that disturbed circadian rhythmicity in humans can increase the risk of reproductive malfunctions, suggesting a link between the circadian system and ER-mediated transcription pathways. Here, we identify a novel level of regulation of estrogen signaling where ERbeta, but not ERalpha, is controlled by circadian clock proteins. We show that ERbeta mRNA levels fluctuate in different peripheral tissues following a robust circadian pattern, with a peak at the light-dark transition, which is maintained under free-running conditions. Interestingly, this oscillation is abolished in clock-deficient BMAL1 knockout mice. Circadian control of ERbeta expression is exerted through a conserved E-box element in the ERbeta promoter region that recruits circadian regulatory factors. Furthermore, using small interfering RNA-mediated knockdown assays, we show that the expression levels ofthe circadian regulatory factors directly influence estrogen signaling by regulating the intracellular levels of endogenous ERbeta.

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