Ruchaud S, Seité P, Foulkes N S, Sassone-Corsi P, Lanotte M
INSERM U301, Centre G. Hayem, Hôpital St Louis, Paris, France.
Oncogene. 1997 Aug 14;15(7):827-36. doi: 10.1038/sj.onc.1201248.
The cAMP pathway plays a central role in the response to hormonal signals for cell proliferation, differentiation and apoptosis. In IPC-81 leukaemia cells, activation of the cAMP pathway by prostaglandin E1 treatment, or other cAMP-elevating agents, induces apoptosis within 4-6 h. Inhibition of mRNA or protein synthesis during the first 2 h of cAMP induction protects cells from apoptosis, suggesting a requirement for early gene expression. cAMP-dependent protein kinase phosphorylates a class of nuclear factors and thereby regulates the transcription of a specific set of genes. Here we show that CREM (cAMP Responsive Element Modulator) expression is induced rapidly upon prostaglandin E1 treatment of IPC-81 cells. The induced transcripts correspond to the early product ICER (Inducible cAMP Early Repressor). ICER expression remains elevated until the burst of cell death. Protein synthesis inhibitors which prevent cAMP-induced apoptosis also block de novo ICER synthesis. Transfected IPC-81 cell lines, constitutively expressing high level of ICER are resistant to cAMP-induced cell death. In these transfected cells, cAMP fails to upregulate the ICER transcripts demonstrating that ICER exerts strongly its repressor function on CRE-containing genes. That an early expression of ICER blocks apoptosis, suggests that gene repression by endogenous ICER in IPC-81 is insufficient or occurs too late to protect cells against death. ICER transfected cells rescued from cAMP-induced apoptosis are growth arrested. It shows for the first time that CREM activation directly participates to the decision of the cell to die. ICER, by sequentially repressing distinct sets of CRE-containing genes could modulate cell fate.
环磷酸腺苷（cAMP）信号通路在细胞对激素信号作出的增殖、分化及凋亡反应中起核心作用。在IPC - 81白血病细胞中，用前列腺素E1处理或其他能升高cAMP的试剂激活cAMP信号通路后，4 - 6小时内会诱导细胞凋亡。在cAMP诱导的最初2小时内抑制mRNA或蛋白质合成可保护细胞免于凋亡，这表明早期基因表达是必需的。cAMP依赖性蛋白激酶使一类核因子磷酸化，从而调节一组特定基因的转录。在此我们表明，用前列腺素E1处理IPC - 81细胞后，CREM（cAMP反应元件调节因子）的表达会迅速被诱导。诱导产生的转录本对应于早期产物ICER（可诱导的cAMP早期阻遏物）。ICER的表达在细胞死亡爆发前一直保持升高。能阻止cAMP诱导的细胞凋亡的蛋白质合成抑制剂也会阻断ICER的从头合成。持续高水平表达ICER的转染IPC - 81细胞系对cAMP诱导的细胞死亡具有抗性。在这些转染细胞中，cAMP无法上调ICER转录本，这表明ICER对含CRE的基因发挥了强大的阻遏功能。ICER的早期表达能阻断细胞凋亡，这表明IPC - 81细胞中内源性ICER的基因阻遏作用不足或发生得太晚，无法保护细胞免于死亡。从cAMP诱导的细胞凋亡中拯救出来的ICER转染细胞生长停滞。这首次表明CREM激活直接参与了细胞死亡的决定。ICER通过依次抑制不同的含CRE基因集，可能会调节细胞命运。
