Mitf cooperates with Rb1 and activates p21Cip1 expression to regulate cell cycle progression
Mitf cooperates with Rb1 and activates p21Cip1 expression to regulate cell cycle progression
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DOI：
10.1038/nature03269
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发表时间：
2005-02-17
期刊：
影响因子：
64.8
通讯作者：
Goding, CR
中科院分区：
文献类型：
--
作者：
Carreira, S;Goodall, J;Goding, CR
使黑素母细胞和黑素瘤细胞增殖的调控机制可能相关，但到目前为止，尚未发现黑素细胞谱系特有的细胞周期进程关键调节因子。小眼畸形相关转录因子Mitf在黑素母细胞和黑素细胞的存活及分化中具有关键但尚不明确的作用。在此我们表明，Mitf可作为一种新型的抗增殖转录因子，能够诱导G1细胞周期停滞，这依赖于Mitf介导的p21(Cip1)（CDKN1A）细胞周期蛋白依赖性激酶抑制剂基因的激活。此外，Mitf与视网膜母细胞瘤蛋白Rb1之间的协同作用增强了Mitf激活转录的能力。结果表明，Mitf介导的p21(Cip1)表达激活以及随之而来的Rb1的低磷酸化将有助于细胞周期退出和分化程序的激活。与黑素瘤相关的基因突变，如INK4a或BRAF，它们分别影响Mitf与Rb1的协同作用或Mitf的稳定性，将损害Mitf介导的细胞周期控制。
The controls that enable melanoblasts and melanoma cells to proliferate are likely to be related, but so far no key regulator of cell cycle progression specific to the melanocyte lineage has been identified. The microphthalmia-associated transcription factor Mitf has a crucial but poorly defined role in melanoblast and melanocyte survival and in differentiation(1). Here we show that Mitf can act as a novel anti-proliferative transcription factor able to induce a G1 cell-cycle arrest that is dependent on Mitf-mediated activation of the p21(Cip1) (CDKN1A) cyclin-dependent kinase inhibitor gene. Moreover, cooperation between Mitf and the retinoblastoma protein Rb1 potentiates the ability of Mitf to activate transcription. The results indicate that Mitf-mediated activation of p21(Cip1) expression and consequent hypophosphorylation of Rb1 will contribute to cell cycle exit and activation of the differentiation programme. The mutation of genes associated with melanoma, such as INK4a or BRAF that would affect either Mitf cooperation with Rb1 or Mitf stability respectively, would impair Mitf-mediated cell cycle control.