Department of Intracellular Signaling and Transport, Institute of Cytology RAS, St. Petersburg, Russian Federation.
Biochem Biophys Res Commun. 2013 Jan 4;430(1):331-5. doi: 10.1016/j.bbrc.2012.11.041. Epub 2012 Nov 23.
While epidermal growth factor (EGF) is a well known mitogen, high doses of EGF result in a paradoxical apoptotic response in the cells that overexpress EGF receptor such as A431 epidermoid carcinoma cells. EGF-induced apoptosis in A431 cells is dependent upon activation of transcription factor STAT1. In this study, we demonstrate that p38 MAP kinase is another important mediator of EGF-dependent pro-apoptotic response in A431 cells. By utilizing p38 MAP kinase inhibitors, SB203580 and BIRB0796, we significantly reduced the integral growth-inhibiting as well as pro-apoptotic effects of EGF. Moreover, we observed that inhibition of p38 MAP kinase markedly decreased phosphorylation of tyrosine 701 in STAT1, while neither EGF-induced accumulation nor serine phosphorylation of STAT1 was decreased. We propose that p38 MAP kinase mediates STAT1 tyrosine phosphorylation, thereby enforcing EGF-induced apoptosis.
虽然表皮生长因子（EGF）是一种众所周知的有丝分裂原，但高剂量的 EGF 会导致过度表达 EGF 受体的细胞（如 A431 表皮样癌细胞）产生矛盾的凋亡反应。EGF 在 A431 细胞中诱导的细胞凋亡依赖于转录因子 STAT1 的激活。在这项研究中，我们证明 p38 MAP 激酶是 A431 细胞中 EGF 依赖性促凋亡反应的另一个重要介质。通过利用 p38 MAP 激酶抑制剂 SB203580 和 BIRB0796，我们显著降低了 EGF 的整体生长抑制和促凋亡作用。此外，我们观察到抑制 p38 MAP 激酶会显著降低 STAT1 酪氨酸 701 的磷酸化，而 EGF 诱导的 STAT1 积累或丝氨酸磷酸化并没有减少。我们提出 p38 MAP 激酶介导 STAT1 酪氨酸磷酸化，从而强制执行 EGF 诱导的细胞凋亡。
