Coffer P J, Burgering B M, Peppelenbosch M P, Bos J L, Kruijer W
Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Utrecht.
Oncogene. 1995 Aug 3;11(3):561-9.
The exposure of mammalian cells to ultraviolet radiation (UV) may lead to DNA damage resulting in mutation and thus possibly cancer, while irradiation can further act as a potent tumor promoter. In addition UV induces p21ras-mediated signalling leading to activation of transcription factors such as AP-1 and NF-kappa B, as well as activation of the Src tyrosine kinase. This 'UV-response' has been well studied in mammalian cells and furthermore is conserved in yeast, however the most upstream components of this signal transduction pathway have remained elusive. Here we show that UV rapidly activates both the EGF receptor and insulin receptor, as shown by tyrosine phosphorylation of these receptors. We demonstrate that this activation is due to autophosphorylation as it only occurs in cells containing receptors with a functional kinase domain. We have further analysed the propagation of the UV-induced signal to downstream events such as, IRS-1 and Shc tyrosine phosphorylation, phosphatidylinositol 3-kinase activation, leukotriene synthesis, MAP kinase activation and gene induction all of which are activated by UV irradiation. Importantly, we demonstrate that in cells expressing a 'kinase-dead' receptor mutant the UV-response is inhibited, blocking leukotriene synthesis, MAP kinase activation and transcriptional induction. Furthermore, prior-stimulation of cells with UV appears to reduce further responsiveness to addition of growth factor suggesting a common signaling pathway. These data demonstrate a critical role for receptor-mediated events in regulating the response mammalian cells to UV exposure.
哺乳动物细胞暴露于紫外线（UV）下可能导致DNA损伤，进而引发突变，甚至可能引发癌症，同时辐射还可进一步充当强效的肿瘤促进剂。此外，紫外线会诱导p21ras介导的信号传导，导致转录因子如AP - 1和核因子κB的激活，以及Src酪氨酸激酶的激活。这种“紫外线反应”在哺乳动物细胞中已得到充分研究，并且在酵母中也保守存在，然而该信号转导途径的最上游成分仍然难以捉摸。在此我们表明，紫外线能迅速激活表皮生长因子（EGF）受体和胰岛素受体，这些受体的酪氨酸磷酸化即为证明。我们证明这种激活是由于自身磷酸化，因为它只发生在含有具有功能性激酶结构域受体的细胞中。我们进一步分析了紫外线诱导信号向下游事件的传导，如下游事件包括胰岛素受体底物-1（IRS - 1）和生长因子结合蛋白Shc的酪氨酸磷酸化、磷脂酰肌醇3激酶激活、白三烯合成、丝裂原活化蛋白激酶（MAP激酶）激活以及基因诱导，所有这些都会被紫外线照射激活。重要的是，我们证明在表达“激酶失活”受体突变体的细胞中，紫外线反应受到抑制，白三烯合成、MAP激酶激活和转录诱导均被阻断。此外，用紫外线预先刺激细胞似乎会降低其对添加生长因子的进一步反应性，这表明存在一条共同的信号通路。这些数据证明了受体介导的事件在调节哺乳动物细胞对紫外线暴露反应中的关键作用。
