咖啡因与肿瘤发生使用同样的信号途径

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The authors of this month's Editor's Choice paper suggest that caffeine mimics an endogenous pathway that is activated for certain cancers.

The paper, from the journal Molecular Cell Biology, has been evaluated as an Exceptional article by Samuel Gunderson of the Cell Biology Faculty, who writes, \"Caffeine, a widely consumed psychoactive \"drug\", is found to induce alternative splicing of the KLF6 tumor suppressor gene as well as a subset of human genes whose alternative splicing is linked to cancer.\"




Caffeine Regulates Alternative Splicing in a Subset of Cancer-Associated Genes: a Role for SC35

Alternative splicing of pre-mRNA contributes significantly to human proteomic complexity, playing a key role in development, gene expression and, when aberrant, human disease onset. Many of the factors involved in alternative splicing have been identified, but little is known about their regulation. Here we report that caffeine regulates alternative splicing of a subset of cancer-associated genes, including the tumor suppressor KLF6. This regulation is at the level of splice site selection, occurs rapidly and reversibly, and is concentration dependent. We have recapitulated caffeine-induced alternative splicing of KLF6 using a cell-based minigene assay and identified a \"caffeine response element\" within the KLF6 intronic sequence. Significantly, a chimeric minigene splicing assay demonstrated that this caffeine response element is functional in a heterologous context; similar elements exist within close proximity to caffeine-regulated exons of other genes in the subset. Furthermore, the SR splicing factor, SC35, was shown to be required for induction of the alternatively spliced KLF6 transcript. Importantly, SC35 is markedly induced by caffeine, and overexpression of SC35 is sufficient to mimic the effect of caffeine on KLF6 alternative splicing. Taken together, our data implicate SC35 as a key player in caffeine-mediated splicing regulation. This novel effect of caffeine provides a valuable tool for dissecting the regulation of alternative splicing of a large gene subset and may have implications with respect to splice variants associated with disease states.

咖啡因调节癌相关基因亚型的选择性剪接作用：SC35的作用

前mRNA的选择性剪接在人蛋白分子复合体的形成中起重要作用，在生长、基因表达中起重要作用，当其突变时，人类就发生疾病。很多影响选择性剪接过程的因素已经被确定，但是这些因素的调节作用则认识得很少。在这里，我们报道了咖啡因调节癌相关基因亚型（包括抑癌基因KLF6）的情况。这种调节是在剪接位点的选择水平上的调节，发生迅速，而且可逆转的、是浓度依赖性的。我们运用细胞小基因分析实验复制了抑癌基因KLF6的咖啡因诱导的选择性剪接情况，确定了咖啡因的反应元件在KLF6的内含子序列里。不同的是，嵌合体小基因剪接实验证明，这种咖啡因反应元件在不同的遗传背景下是功能性的。相似的元件在接近咖啡因调节的其它基因亚型的外显子附近同样存在。而且，SR剪接因子--SC35，在诱导经过选择性剪接的KLF6转录中是必需的。重要的是，SC35可以被咖啡因明显的诱导，而且SC35的过度表达能够模拟咖啡因对KLF6的选择性剪接作用。总之，我们的研究资料提示，SC35在咖啡因介导的剪接调节作用中扮演重要角色。咖啡因的这种新的作用，为仔细的分析一大批基因亚型的选择性剪接作用的调节机制提供有价值的工具，可能也为研究与疾病相关的剪接变异提供参考。