Wilson N J, Jaworowski A, Ward A C, Hamilton J A
University of Melbourne, Department of Medicine, Royal Melbourne Hospital, Parkville, Australia.
Biochem Biophys Res Commun. 1998 Mar 17;244(2):475-80. doi: 10.1006/bbrc.1998.8290.
Inhibition of MAPK by elevated intracellular cAMP has often been correlated with suppression of growth factor-induced proliferation. However, in murine bone marrow-derived macrophages (BMM) we show that the cAMP analogue, 8-bromo cAMP (8BrcAMP) (1mM), despite being a dramatic G1 phase proliferation inhibitor, increased ERK activity both in the absence and presence of CSF-1; these increases were blocked by PD98059 (100 microM) suggesting MEK dependence. In contrast, CSF-1-stimulated p21Ras activity was blocked by 8BrcAMP thus correlating with the inhibition of proliferation. This is the first report to indicate that elevated intracellular cAMP can activate ERK activity while inhibiting proliferation and the data support the concept in CSF-1-treated macrophages of Ras-independent activation of ERK activity. It was also found that the acute but not the sustained elevation of c-fos mRNA expression due to 8BrcAMP was also MEK dependent indicating that there are separate pathways controlling c-fos mRNA expression in BMM.
细胞内cAMP升高对丝裂原活化蛋白激酶（MAPK）的抑制作用常常与生长因子诱导的增殖抑制相关。然而，在小鼠骨髓来源的巨噬细胞（BMM）中，我们发现cAMP类似物8-溴-cAMP（8BrcAMP）（1mM）尽管是一种显著的G1期增殖抑制剂，但无论有无集落刺激因子-1（CSF-1），它都会增加细胞外信号调节激酶（ERK）的活性；这些增加被PD98059（100微摩尔）阻断，表明其依赖于丝裂原活化蛋白激酶激酶（MEK）。相反，8BrcAMP阻断了CSF-1刺激的p21Ras活性，因此与增殖抑制相关。这是第一份表明细胞内cAMP升高可在抑制增殖的同时激活ERK活性的报告，并且这些数据支持在CSF-1处理的巨噬细胞中ERK活性存在不依赖Ras激活的概念。还发现，8BrcAMP引起的c-fos信使核糖核酸（mRNA）表达的急性而非持续性升高也依赖于MEK，这表明在BMM中有控制c-fos mRNA表达的不同途径。
