Microphthalmia-Associated Transcription Factor Controls the DNA Damage Response and a Lineage-Specific Senescence Program in Melanomas
Microphthalmia-Associated Transcription Factor Controls the DNA Damage Response and a Lineage-Specific Senescence Program in Melanomas
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DOI：
10.1158/0008-5472.can-09-2913
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发表时间：
2010-05-01
期刊：
影响因子：
11.2
通讯作者：
Bertolotto, Corine
中科院分区：
文献类型：
--
作者：
Giuliano, Sandy;Cheli, Yann;Bertolotto, Corine
细胞凋亡和衰老是细胞故障保护程序，可以抵消癌细胞中观察到的过度有丝分裂信号传导。黑色素瘤以其对细胞凋亡过程的抵抗而闻名。因此，对于黑色素瘤的衰老仍然知之甚少，但它可以被视为一种治疗替代方案。小眼相关转录因子（MITF）的M转录物在黑色素细胞中特异性表达，在黑色素瘤增殖中发挥着关键作用，其特异性抑制与G（0）-G（1）生长停滞有关。有趣的是，在衰老的黑素细胞中已经描述了 MITF 表达的减少，并且我们观察到暴露于诱导其衰老的化疗药物的黑素瘤细胞中 MITF 表达受到抑制。因此，所有这些观察结果都对 MITF 在控制黑色素瘤细胞衰老中的作用提出了质疑。在这里，我们报告黑色素瘤细胞中 MITF 的长期消耗会触发衰老程序，其特征是与持续生长停滞相关的典型形态和生化变化。此外，我们发现 MITF 沉默的细胞参与 DNA 损伤反应 (DDR) 信号通路，导致 p53 上调，这是进入衰老的关键。这项研究揭示了谱系限制的 DDR/p53 信号通路的存在，该通路被 MITF 抑制，以防止衰老并促进黑色素瘤细胞增殖。癌症研究； 70(9)；3813-22。 (C) 2010 AACR。
Apoptosis and senescence are cellular failsafe programs that counteract excessive mitogenic signaling observed in cancer cells. Melanoma is known for its notorious resistance to apoptotic processes; therefore, senescence, which remains poorly understood in melanomas, can be viewed as a therapeutic alternative. Microphthalmia-associated transcription factor (MITF), in which its M transcript is specifically expressed in melanocyte cells, plays a critical role in melanoma proliferation, and its specific inhibition is associated with G(0)-G(1) growth arrest. Interestingly, decreased MITF expression has been described in senescent melanocytes, and we have observed an inhibition of MITF expression in melanoma cells exposed to chemotherapeutic drugs that induce their senescence. All these observations thereby question the role of MITF in controlling senescence in melanoma cells. Here, we report that long-term depletion of MITF in melanoma cells triggers a senescence program characterized by typical morphologic and biochemical changes associated with a sustained growth arrest. Further, we show that MITF-silenced cells engage a DNA damage response (DDR) signaling pathway, leading to p53 upregulation, which is critically required for senescence entry. This study uncovers the existence of a lineage-restricted DDR/p53 signaling pathway that is inhibited by MITF to prevent senescence and favor melanoma cell proliferation. Cancer Res; 70(9);3813-22. (C) 2010 AACR.