Institute of Pharmacology and Toxicology, University of Münster, Münster, Germany.
Faculty of Life Sciences, Toyo University, Gunma, Japan.
FASEB J. 2020 Aug;34(8):11272-11291. doi: 10.1096/fj.201902301RR. Epub 2020 Jun 30.
ICER (inducible cAMP early repressor) isoforms are transcriptional repressors encoded by the Crem (cAMP responsive element modulator) gene. They were linked to the regulation of a multitude of cellular processes and pathophysiological mechanisms. Here, we show for the first time that two independent induction patterns for CREM repressor isoforms exist in the heart, namely for ICER and smICER (small ICER), which are induced in response to β-adrenergic stimulation in a transient- and saturation-like manner, respectively. This time-shifted induction pattern, driven by two internal promoters in the Crem gene, leads to the predominant transcription of smIcer after prolonged β-adrenergic stimulation. Using an ICER knockout mouse model with preserved smICER induction, we show that the transient-like induction of Icer itself has minor effects on gene regulation, cardiac hypertrophy or contractile function in the heart. We conclude that the functions previously linked to ICER may be rather attributed to smICER, also beyond the cardiac background.
ICER（诱导型 cAMP 早期阻遏物）异构体是由 Crem（cAMP 反应元件调节剂）基因编码的转录阻遏物。它们与多种细胞过程和病理生理机制的调节有关。在这里，我们首次表明，CREM 阻遏物异构体在心脏中存在两种独立的诱导模式，即 ICER 和 smICER（小 ICER），它们分别以瞬时和饱和样方式响应β-肾上腺素刺激而被诱导。这种由 Crem 基因中的两个内部启动子驱动的时移诱导模式导致在长时间β-肾上腺素刺激后 smIcer 的主要转录。使用具有保留 smICER 诱导的 ICER 敲除小鼠模型，我们表明 Icer 的瞬时样诱导本身对心脏中的基因调控、心肌肥厚或收缩功能的影响较小。我们得出结论，以前与 ICER 相关的功能可能更多地归因于 smICER，甚至超出了心脏背景。
