Thompson M A, Ginty D D, Bonni A, Greenberg M E
Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115.
J Biol Chem. 1995 Mar 3;270(9):4224-35. doi: 10.1074/jbc.270.9.4224.
A mechanism by which voltage-sensitive Ca2+ channel (VSCC) activation triggers c-fos transcription has been characterized. Ca2+ influx through VSCCs stimulates phosphorylation of the transcription factor cAMP response element-binding protein (CREB) on serine 133 leading to an increase in the formation of transcription complexes that can elongate through a transcription pause site within the c-fos gene. Ca(2+)-stimulated CREB serine 133 phosphorylation is mediated by a Ca(2+)-activated kinase and is not dependent on the cAMP-dependent protein kinase (PKA). While necessary for c-fos transcriptional induction following VSCC opening, CREB serine 133 phosphorylation is not sufficient for transcriptional activation. A second, PKA-dependent event is required. Following induction, c-fos transcription is rapidly down-regulated. Dephosphorylation of CREB serine 133 parallels and likely mediates the transcriptional shut-off event. These results suggest that the phosphorylation and dephosphorylation of CREB controls its ability to regulate transcription in membrane-depolarized cells and that multiple pathways contribute to Ca(2+)-activated gene expression.
一种电压敏感型Ca2+通道（VSCC）激活触发c-fos转录的机制已得到阐明。通过VSCC的Ca2+内流刺激转录因子cAMP反应元件结合蛋白（CREB）丝氨酸133位点的磷酸化，导致转录复合物形成增加，该复合物可通过c-fos基因内的转录暂停位点进行延伸。Ca2+刺激的CREB丝氨酸133磷酸化由Ca2+激活的激酶介导，且不依赖于cAMP依赖性蛋白激酶（PKA）。虽然CREB丝氨酸133磷酸化对于VSCC开放后的c-fos转录诱导是必需的，但它不足以实现转录激活。还需要第二个依赖PKA的事件。诱导后，c-fos转录迅速下调。CREB丝氨酸133的去磷酸化与转录关闭事件平行且可能介导该事件。这些结果表明，CREB的磷酸化和去磷酸化控制其在膜去极化细胞中调节转录的能力，并且多种途径参与Ca2+激活的基因表达。
