Foulkes N S, Borjigin J, Snyder S H, Sassone-Corsi P
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.
Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):14140-5. doi: 10.1073/pnas.93.24.14140.
Transcription factor cAMP-responsive element modulator (CREM) plays a key physiological and developmental role within the hypothalamic-pituitary-gonadal axis. The use of an alternative, intronic promoter within the CREM gene is responsible for the production of a cAMP-inducible repressor, inducible cAMP early repressor (ICER). ICER negatively autoregulates the ICER promoter, thus generating a feedback loop. We have previously documented a striking, clock-driven circadian fluctuation of CREM expression in the pineal gland. Oscillating ICER levels tightly correlate with fluctuations in the synthesis of the pineal hormone melatonin, whose production is also driven by the endogenous clock. Melatonin in turn regulates the hypothalamic-pituitary axis. The enzyme serotonin N-acetyltransferase (NAT) catalyzes the rate limiting step in melatonin synthesis. Thus, oscillations in NAT levels determine the circadian synthesis of melatonin. Here we demonstrate that NAT expression is dramatically increased in CREM-deficient mice that we have generated by homologous recombination. Characterization of the NAT promoter shows the presence of a ICER binding site. In addition, transfection studies show that ICER powerfully represses NAT transcription. Our results implicate CREM as a central regulator of output functions of the clock. Indeed, CREM acts as a key regulator of oscillatory hormonal synthesis.
转录因子环磷酸腺苷反应元件调节因子（CREM）在下丘脑-垂体-性腺轴中发挥关键的生理和发育作用。CREM基因内一个替代性的内含子启动子负责产生一种环磷酸腺苷诱导型阻遏物，即诱导型环磷酸腺苷早期阻遏物（ICER）。ICER对ICER启动子进行负向自动调节，从而形成一个反馈回路。我们之前记录了松果体中CREM表达存在显著的、由生物钟驱动的昼夜节律波动。振荡的ICER水平与松果体激素褪黑素合成的波动紧密相关，褪黑素的产生同样由内源性生物钟驱动。褪黑素进而调节下丘脑-垂体轴。血清素N-乙酰转移酶（NAT）催化褪黑素合成中的限速步骤。因此，NAT水平的振荡决定了褪黑素的昼夜合成。在此我们证明，在我们通过同源重组产生的CREM缺陷型小鼠中，NAT表达显著增加。对NAT启动子的特性分析显示存在一个ICER结合位点。此外，转染研究表明ICER能强力抑制NAT转录。我们的结果表明CREM是生物钟输出功能的核心调节因子。实际上，CREM作为振荡性激素合成的关键调节因子发挥作用。
