MITF links differentiation with cell cycle arrest in melanocytes by transcriptional activation of INK4A.
MITF links differentiation with cell cycle arrest in melanocytes by transcriptional activation of INK4A.
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DOI：
10.1083/jcb.200410115
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发表时间：
2005-01-03
期刊：
影响因子：
--
通讯作者：
Harbour JW
中科院分区：
文献类型：
--
作者：
Loercher AE;Tank EM;Delston RB;Harbour JW
大多数细胞的正确分化需要细胞周期退出，并且对于正常发育、组织稳态和肿瘤抑制至关重要。然而，将细胞周期退出与分化联系起来的机制仍知之甚少。在这里，我们发现主要的黑色素细胞分化因子小眼转录因子（MITF）通过激活细胞周期抑制剂INK4A（一种在黑色素瘤中经常发生突变的肿瘤抑制因子）来调节细胞周期退出。 MITF 结合 INK4A 启动子，激活 p16Ink4a mRNA 和蛋白表达，并诱导视网膜母细胞瘤蛋白低磷酸化，从而触发细胞周期停滞。 INK4A 的激活是黑素细胞有效分化所必需的。有趣的是，MITF 也是维持成熟黑素细胞中 INK4A 表达所必需的，从而产生选择性压力，通过灭活 INK4A 来逃避生长抑制。这些发现表明，INK4A 可以受到分化因子的调节，在黑色素细胞分化和细胞周期退出之间建立机制联系，并可能解释黑色素瘤中 INK4A 突变发生的组织特异性趋势。
Cell cycle exit is required for proper differentiation in most cells and is critical for normal development, tissue homeostasis, and tumor suppression. However, the mechanisms that link cell cycle exit with differentiation remain poorly understood. Here, we show that the master melanocyte differentiation factor, microphthalmia transcription factor (MITF), regulates cell cycle exit by activating the cell cycle inhibitor INK4A, a tumor suppressor that frequently is mutated in melanomas. MITF binds the INK4A promoter, activates p16Ink4a mRNA and protein expression, and induces retinoblastoma protein hypophosphorylation, thereby triggering cell cycle arrest. This activation of INK4A was required for efficient melanocyte differentiation. Interestingly, MITF was also required for maintaining INK4A expression in mature melanocytes, creating a selective pressure to escape growth inhibition by inactivating INK4A. These findings demonstrate that INK4A can be regulated by a differentiation factor, establish a mechanistic link between melanocyte differentiation and cell cycle exit, and potentially explain the tissue-specific tendency for INK4A mutations to occur in melanoma.
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影响因子：
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作者：
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DOI：
10.1073/pnas.2431391100
发表时间：
2003-12-09
影响因子：
11.1
作者：
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通讯作者：
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