Paronetto Maria Paola, Passacantilli Ilaria, Sette Claudio
Department of Movement, Human and Health Sciences, University of Rome 'Foro Italico', Rome 00135, Italy.
Laboratories of Cellular and Molecular Neurobiology and of Neuroembryology, Fondazione Santa Lucia, Rome 00143, Italy.
Cell Death Differ. 2016 Dec;23(12):1919-1929. doi: 10.1038/cdd.2016.91. Epub 2016 Sep 30.
Most human genes encode multiple mRNA variants and protein products through alternative splicing of exons and introns during pre-mRNA processing. In this way, alternative splicing amplifies enormously the coding potential of the human genome and represents a powerful evolutionary resource. Nonetheless, the plasticity of its regulation is prone to errors and defective splicing underlies a large number of inherited and sporadic diseases, including cancer. One key cellular process affected by alternative splicing is the programmed cell death or apoptosis. Many apoptotic genes encode for splice variants having opposite roles in cell survival. This regulation modulates cell and tissue homeostasis and is implicated in both developmental and pathological processes. Furthermore, recent evidence has also unveiled splicing-mediated regulation of genes involved in autophagy, another essential process for tissue homeostasis. In this review, we highlight some of the best-known examples of alternative splicing events involved in cell survival. Emphasis is given to the role of this regulation in human cancer and in the response to chemotherapy, providing examples of how alternative splicing of apoptotic genes can be exploited therapeutically.
大多数人类基因通过前体mRNA加工过程中外显子和内含子的可变剪接来编码多种mRNA变体和蛋白质产物。通过这种方式，可变剪接极大地扩展了人类基因组的编码潜力，并代表了一种强大的进化资源。尽管如此，其调控的可塑性容易出错，剪接缺陷是包括癌症在内的大量遗传性和散发性疾病的基础。可变剪接影响的一个关键细胞过程是程序性细胞死亡或凋亡。许多凋亡基因编码在细胞存活中具有相反作用的剪接变体。这种调控调节细胞和组织的稳态，并参与发育和病理过程。此外，最近的证据还揭示了剪接介导的对自噬相关基因的调控，自噬是组织稳态的另一个重要过程。在这篇综述中，我们重点介绍了一些参与细胞存活的最著名的可变剪接事件实例。重点阐述了这种调控在人类癌症和化疗反应中的作用，并举例说明了凋亡基因的可变剪接如何被用于治疗。
