Institute of Toxicology, Medical Center of the Johannes Gutenberg-University, Obere Zahlbacherstr, 67, 55131 Mainz, Germany.
Cell Commun Signal. 2012 Mar 9;10:6. doi: 10.1186/1478-811X-10-6.
p38 MAP kinase is known to be activated by cellular stress finally leading to cell cycle arrest or apoptosis. Furthermore, a tumour suppressor role of p38 MAPK has been proposed. In contrast, a requirement of p38 for proliferation has also been described. To clarify this paradox, we investigated stress- and mitogen-induced p38 signalling in the same cell type using fibroblasts. We demonstrate that - in the same cell line - p38 is activated by mitogens or cellular stress, but p38-dependent signalling is different. Exposure to cellular stress, such as anisomycin, leads to a strong and persistent p38 activation independent of GTPases. As a result, MK2 and downstream the transcription factor CREB are phosphorylated. In contrast, mitogenic stimulation results in a weaker and transient p38 activation, which upstream involves small GTPases and is required for cyclin D1 induction. Consequently, the retinoblastoma protein is phosphorylated and allows G1/S transition. Our data suggest a dual role of p38 and indicate that the level and/or duration of p38 activation determines the cellular response, i.e either proliferation or cell cycle arrest.
p38 MAP 激酶已知可被细胞应激激活，最终导致细胞周期停滞或细胞凋亡。此外，还提出了 p38 MAPK 的肿瘤抑制作用。相比之下，也有研究描述了 p38 对增殖的需求。为了解决这一矛盾，我们使用成纤维细胞研究了应激和有丝分裂原诱导的 p38 信号通路。我们证明，在同一种细胞系中，p38 被有丝分裂原或细胞应激激活，但 p38 依赖性信号通路不同。暴露于细胞应激，如 anisomycin，会导致 p38 的强烈且持久激活，而这种激活与 GTP 酶无关。结果，MK2 和下游转录因子 CREB 被磷酸化。相比之下，有丝分裂刺激会导致较弱且短暂的 p38 激活，其上游涉及小 GTP 酶，这对于 cyclin D1 的诱导是必需的。因此，视网膜母细胞瘤蛋白被磷酸化，从而允许 G1/S 期过渡。我们的数据表明 p38 具有双重作用，并表明 p38 的激活水平和/或持续时间决定了细胞的反应，即增殖或细胞周期停滞。
