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MITF and cell proliferation: the role of alternative splice forms

机译：MITF和细胞增殖：替代剪接形式的作用

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Recent studies show that the melanocyte transcription factor MITF not only activates differentiation genes but also genes involved in the regulation of the cell cycle, suggesting that it provides a link between cell proliferation and differentiation. MITF, however, comes in a variety of splice isoforms with potentially distinct biological activities. In particular, there are two isoforms, (-) and (+) MITF, that differ in six residues located upstream of the DNA binding basic domain and show slight differences in the efficiency with which they bind to target DNA. Using in vitro BrdU incorporation assays and FACS analysis in transiently transfected cells, we show that (+) MITF has a strong inhibitory effect on DNA synthesis while (-) MITF has none or only a mild one. The strong inhibitory activity of (+) MITF is not influenced by a number of mutations that modulate MITF's transcriptional activities and is independent of the protein's carboxyl terminus but dependent on its aminoterminus. A further dissection of the molecule points to the importance of an aminoterminal serine, serine-73, which in both isoforms is phosphorylated to comparable degrees. The results suggest that one or several aminoterminal domains cooperate with the alternatively spliced hexapeptide to render MITF anti-proliferative in a way that does not depend on direct E box binding.
机译：最近的研究表明，黑素细胞转录因子MITF不仅激活分化基因，而且还激活参与细胞周期调控的基因，这表明它提供了细胞增殖与分化之间的联系。但是，MITF出现了多种剪接亚型，具有潜在不同的生物活性。特别是，有两个同工型（-）和（+）MITF，它们位于DNA结合碱性结构域上游的六个残基不同，并且在结合靶DNA的效率上显示出细微差别。在瞬时转染的细胞中使用体外BrdU掺入测定和FACS分析，我们显示（+）MITF对DNA合成具有很强的抑制作用，而（-）MITF没有或只有轻度抑制作用。 （+）MITF的强抑制活性不受调节MITF转录活性的许多突变的影响，并且独立于蛋白质的羧基末端，但取决于其氨基末端。分子的进一步解剖指出了氨基末端丝氨酸73的重要性，丝氨酸73在两种同工型中都被磷酸化到可比的程度。结果表明一个或几个氨基末端结构域与交替剪接的六肽协同作用，以不依赖于直接E盒结合的方式使MITF具有抗增殖性。

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