Mitf regulation of Dia1 controls melanoma proliferation and invasiveness
Mitf regulation of Dia1 controls melanoma proliferation and invasiveness
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DOI：
10.1101/gad.406406
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发表时间：
2006-12-15
影响因子：
10.5
通讯作者：
Goding, Colin R.
中科院分区：
文献类型：
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作者：
Carreira, Suzanne;Goodall, Jane;Goding, Colin R.
人们普遍认为，具有转移特性（如侵袭性和基质金属蛋白酶表达）的细胞是通过遗传不稳定性和“克隆进化”引起的遗传病变的逐步积累而产生的。“相比之下，我们在这里表明，在黑色素瘤中，侵袭性可以通过小眼症相关转录因子Mitf通过调节DIAPH 1基因来调节，该基因编码透明相关的Dia 1，促进肌动蛋白聚合并协调细胞周边的肌动蛋白细胞骨架和微管网络。低Mitf水平导致Dia 1的下调、肌动蛋白细胞骨架的重组和ROCK依赖性侵袭性增加，而Mitf表达增加导致侵袭性降低。重要的是，Mitf对Dia 1的调节也控制p27（Kip 1）降解，使得Mitf水平降低导致p27（Kip 1）依赖性G1期阻滞。因此，Mitf，通过调节Dia 1，可以抑制侵袭和促进增殖。结果意味着决定Mitf活性的环境线索库的变化将通过动态表观遗传机制决定黑色素瘤细胞的分化、增殖和侵袭/迁移潜力。
It is widely held that cells with metastatic properties such as invasiveness and expression of matrix metalloproteinases arise through the stepwise accumulation of genetic lesions arising from genetic instability and "clonal evolution." By contrast, we show here that in melanomas invasiveness can be regulated epigenetically by the microphthalmia-associated transcription factor, Mitf, via regulation of the DIAPH1 gene encoding the diaphanous-related formin Dia1 that promotes actin polymerization and coordinates the actin cytoskeleton and microtubule networks at the cell periphery. Low Mitf levels lead to down-regulation of Dia1, reorganization of the actin cytoskeleton, and increased ROCK-dependent invasiveness, whereas increased Mitf expression leads to decreased invasiveness. Significantly the regulation of Dia1 by Mitf also controls p27(Kip1)-degradation such that reduced Mitf levels lead to a p27(Kip1)-dependent G1 arrest. Thus Mitf, via regulation of Dia1, can both inhibit invasiveness and promote proliferation. The results imply variations in the repertoire of environmental cues that determine Mitf activity will dictate the differentiation, proliferative, and invasive/migratory potential of melanoma cells through a dynamic epigenetic mechanism.