Gilley Rebecca, March H Nikki, Cook Simon J
Laboratory of Molecular Signalling, The Babraham Institute, Babraham Research Campus, Cambridge, UK.
Cell Signal. 2009 Jun;21(6):969-77. doi: 10.1016/j.cellsig.2009.02.006. Epub 2009 Feb 25.
Growth factor-stimulated expression and activation of c-Fos is regulated by the ERK1/2 pathway. However, recent reports have also suggested a prominent role for the closely related ERK5 pathway in regulating the expression, transcriptional activation and nuclear localization of c-Fos. Here we have compared the role of ERK1/2 and ERK5 in regulating c-Fos using a combination of conditional protein kinases, selective biochemical inhibitors and ERK5 null fibroblasts. We demonstrate that activation of the ERK1/2 pathway, but not ERK5, is sufficient for c-Fos phosphorylation and transcriptional activation. Furthermore, growth factor-dependent expression of c-Fos is blocked by low doses of PD184352 that selectively inhibit the ERK1/2 pathway but proceeds normally in ERK5-/- 3T9 cells; in addition, nuclear localization of c-Fos is normal in ERK5-/- cells. ERK5-/- cells are, however, defective for c-Jun expression but this is reversed by re-expression of ERK5. In addition to ERK5, neither the JNK nor p38 pathways can substitute for ERK1/2 in the regulation of c-Fos transcriptional activity. These results demonstrate that c-Fos transcriptional activity is not regulated by the ERK5 pathway; rather, of all the MAPKs and SAPKs, c-Fos activation appears to be predominantly linked to the ERK1/2 pathway.
生长因子刺激的c-Fos表达和激活受ERK1/2通路调控。然而，最近的报道也表明，密切相关的ERK5通路在调节c-Fos的表达、转录激活和核定位方面发挥着重要作用。在这里，我们结合条件性蛋白激酶、选择性生化抑制剂和ERK5基因敲除的成纤维细胞，比较了ERK1/2和ERK5在调节c-Fos中的作用。我们证明，ERK1/2通路的激活而非ERK5通路的激活，足以使c-Fos磷酸化和转录激活。此外，低剂量的PD184352可阻断c-Fos的生长因子依赖性表达，该药物选择性抑制ERK1/2通路，但在ERK5基因敲除的3T9细胞中c-Fos的表达正常进行；此外，ERK5基因敲除细胞中c-Fos的核定位正常。然而，ERK5基因敲除细胞的c-Jun表达存在缺陷，但通过重新表达ERK5可使其恢复正常。除ERK5外，JNK和p38通路均不能替代ERK1/2来调节c-Fos的转录活性。这些结果表明，c-Fos的转录活性不受ERK5通路的调控；相反，在所有的丝裂原活化蛋白激酶（MAPK）和应激激活蛋白激酶（SAPK）中，c-Fos的激活似乎主要与ERK1/2通路相关。
