JNK supports survival in melanoma cells by controlling cell cycle arrest and apoptosis
JNK supports survival in melanoma cells by controlling cell cycle arrest and apoptosis
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DOI：
10.1111/j.1755-148x.2008.00466.x
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发表时间：
2008-08-01
影响因子：
4.3
通讯作者：
Mauviel, Alain
中科院分区：
文献类型：
--
作者：
Alexaki, Vasileia-Ismini;Javelaud, Delphine;Mauviel, Alain
JNK1/2蛋白属于应激激活蛋白激酶家族。它们在生长调节中起着复杂的作用，诱导细胞死亡或促进生长。在本报告中，我们提供的证据表明，在人类黑色素瘤细胞中，用小分子抑制剂SP600125抑制JNK主要诱导G2/M阻滞或凋亡，这取决于细胞系。在1205Lu细胞中，JNK抑制通过p53依赖诱导p21（Cip1/Waf1）表达诱导细胞周期阻滞，而在WM983B细胞中，JNK抑制诱导凋亡伴随着p53、Bad和Bax的诱导，而不是p21（Cip1/Waf1）的诱导。用小分子抑制剂SP600125抑制JNK可以减缓所有细胞系的生长，尽管在高磷（P-）JNK1水平的细胞中效果明显更大。通过siRNA寡核苷酸特异性敲低JNK1基因仅在高P-JNK1水平的黑色素瘤细胞系中抑制细胞生长。针对JNK2的sirna在任何测试的细胞系中都没有降低细胞生长。总之，我们的研究结果表明，JNK，特别是JNK1亚型，通过根据细胞环境控制细胞周期进程或凋亡来支持黑色素瘤细胞的生长。
JNK1/2 proteins belong to the family of stress-activated protein kinases. They play a complex role in growth regulation, inducing either cell death or growth support. In this report, we provide evidence that, in human melanoma cells, JNK inhibition with the small molecule inhibitor SP600125 induces either predominantly a G2/M arrest or apoptosis depending on the cell line. In 1205Lu cells, JNK inhibition induced cell cycle arrest through p53-dependent induction of p21(Cip1/Waf1) expression, while in WM983B cells, induction of apoptosis by JNK inhibition was accompanied by p53, Bad and Bax induction, not p21(Cip1/Waf1). JNK inhibition with the small molecule inhibitor SP600125 slowed growth of all cell lines, although the effect was markedly greater in cells exhibiting high phospho- (P-)JNK1 levels. Specific gene knockdown of JNK1 by means of siRNA oligonucleotides inhibited cell growth only in melanoma cell lines exhibiting high P-JNK1 levels. siRNAs directed against JNK2 did not reduce cell growth in any of the cell lines tested. Together, our findings demonstrate that JNK, and in particular the JNK1 isoform, support the growth of melanoma cells, by controlling either cell cycle progression or apoptosis depending on the cellular context.