Role of TRAF2/GCK in melanoma sensitivity to UV-induced apoptosis
Role of TRAF2/GCK in melanoma sensitivity to UV-induced apoptosis
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DOI：
10.1038/sj.onc.1203415
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发表时间：
2000-02-17
期刊：
影响因子：
8
通讯作者：
Ronai, Z
中科院分区：
文献类型：
--
作者：
Ivanov, VN;Kehrl, JH;Ronai, Z
辐射抵抗是人类黑色素瘤的一个标志，然而这种抵抗的机制还不是很清楚。我们最近确定了ATF2在这一过程中的作用，表明压力激酶有助于调节ATF2的稳定性和活性，在获得这种抗性方面发挥了重要作用。在这里，我们证明了TRAF2/GCK的表达和各自活性的变化发生在黑色素瘤的发展过程中，并调节其对紫外线诱导的凋亡的敏感性，比较早期和晚期黑色素瘤细胞发现TRAF2和GCK在早期黑色素瘤中低表达，这与其对紫外线诱导的、肿瘤坏死因子介导的凋亡的抵抗力较差相吻合；强迫表达GCK单独或与TRAF2联合有效地增加JNK和NF-kappaB的活性，这与增强对细胞凋亡的保护是一致的，相反，强迫表达主要的阴性形式的TRAF2或GCK在晚期黑色素瘤细胞中降低了NF-kappa B的活性和Fas的表达，导致紫外线诱导的Fas介导的细胞死亡程度较低。我们的结果说明了一种机制，即保护或促进紫外线诱导的黑色素瘤细胞死亡取决于凋亡级联的性质(肿瘤坏死因子或Fas)和TRAF2/GCK的可用性，TRAF2/GCK的表达在黑色素瘤进展过程中增加。
Radiation resistance is a hallmark of human melanoma, and yet mechanisms underlying this resistance are not well understood. We recently established the role of ATF2 in this process, suggesting that stress kinases, which contribute to regulation of ATF2 stability and activity, play an important role in the acquisition of such resistance. Here we demonstrate that changes in the expression and respective activities of TRAF2/GCK occur during melanoma development and regulate its sensitivity to UV-induced apoptosis, Comparing early- and late-stage melanoma cells revealed low expression of TRAF2 and GCK in early-stage melanoma, which coincided with poor resistance to UV-induced, TNF-mediated apoptosis; forced expression of GCK alone or in combination with TRAF2 efficiently increased JNK and NF-kappa B activities, which coincided with increased protection against apoptosis, Conversely, forced expression of the dominant negative form of TRAF2 or GCK in late-stage melanoma cells reduced NF-kappa B activity and decreased Fas expression, resulting in a lower degree of UV-induced, Fas-mediated cell death. Our results illustrate a mechanism in which protection from, or promotion of, UV-induced melanoma cell death depends on the nature of the apoptotic cascade (TNF or Fas) and on the availability of TRAF2/GCK, whose expression increases during melanoma progression.