Dhar V, Adler V, Lehmann A, Ronai Z
Molecular Carcinogenesis Program, American Health Foundation, Valhalla, New York 10595, USA.
Cell Growth Differ. 1996 Jun;7(6):841-6.
c-jun-NH2 kinases (JNK) are among the UV-activated protein kinases that play an important role in cellular stress response via the phosphorylation of c-jun, ATF2, and p53. Activation of JNK by UV irradiation requires cooperation between membrane and nuclear components, including DNA lesions per se. The role of DNA lesions in JNK activation led us to explore the inducibility of these kinases in cells of repair-deficient patients. Analyses of primary fibroblast cell lines from patients with Cockayne Syndrome of complementation group B (CS-B) revealed poor JNK activation after UV irradiation in four of five cases when compared with three repair-proficient, normal human fibroblast cell lines. Impaired ability to activate JNK persisted at various time points and with different doses of UV irradiation and coincided with failure of in vitro damaged DNA to activate these kinases. In contrast to UV irradiation, other forms of stress, such as H2O2 or heat shock were capable of inducing JNK activation in CS-B cells. Interestingly, when UV irradiation was administered after osmotic shock, it led to JNK activation in CS-B cells, indicating that alternate signal transduction pathways that are activated in response to other forms of stress can potentiate JNK activation by UV irradiation. Unlike CS-B cells, those of other repair-deficient cells, including xeroderma pigmentosum of different complementation groups, revealed proper activation of JNK by UV irradiation. Together, our findings point to deficiency of JNK activation by UV irradiation in CS-B cells, a phenomenon which may be associated with impaired CS-B, the mutant repair gene in these patients.
c-Jun氨基末端激酶（JNK）是紫外线激活的蛋白激酶之一，通过对c-Jun、ATF2和p53的磷酸化作用，在细胞应激反应中发挥重要作用。紫外线照射激活JNK需要膜成分和核成分之间的协同作用，包括DNA损伤本身。DNA损伤在JNK激活中的作用促使我们探索这些激酶在修复缺陷患者细胞中的诱导能力。对互补组B型科凯恩综合征（CS-B）患者的原代成纤维细胞系分析显示，与三种修复功能正常的正常人成纤维细胞系相比，五例中有四例在紫外线照射后JNK激活较差。激活JNK的能力受损在不同时间点和不同剂量紫外线照射下持续存在，并且与体外受损DNA无法激活这些激酶一致。与紫外线照射不同，其他形式的应激，如过氧化氢或热休克能够在CS-B细胞中诱导JNK激活。有趣的是，当在渗透休克后给予紫外线照射时，它会导致CS-B细胞中的JNK激活，这表明响应其他形式应激而激活的替代信号转导途径可以增强紫外线照射对JNK的激活作用。与CS-B细胞不同，其他修复缺陷细胞，包括不同互补组的着色性干皮病细胞，经紫外线照射后显示JNK的正常激活。总之，我们的研究结果表明CS-B细胞中紫外线照射导致JNK激活缺陷，这一现象可能与这些患者中的突变修复基因CS-B功能受损有关。
