![]() We have chosen examples in which there is strong evidence that the new proteins encoded by the aberrantly spliced mRNA confer unique function to the expressing cancer cells. This review is not meant to provide an exhaustive list of all of the genes abnormally spliced in cancer cells, since the number of such genes is well over 100, and a mere listing of those provides no conceptual framework in which to think of the problem. In this review, we will focus on the mechanisms by which splicing has been shown to be abnormal in cancer cells. Emerging data suggest that, at least in some cases, the aberrant mRNAs and their encoded proteins have unique properties that confer new properties of growth, differentiation and other cellular characteristics to the cancer cell. Until recently, it was not clear whether abnormal mRNA splicing was a consequence of transformation, or whether the new RNA and protein isoforms that were produced had actual functional consequences for the cancer cell ( Kim et al., 2008). In cancer cells, normal mRNA splicing can be misregulated by cancer-specific defects in several splicing mechanisms ( Skotheim and Nees, 2007 Srebrow and Kornblihtt, 2006 and references therein). It is this regulation of alternative exon usage that can be defective in cancer cells, with potential transcriptome-wide consequences to gene function. ![]() The higher-order challenge is for the splicing machinery to alter exon usage in alternative splice variants in response to environmental, developmental or tissue-specific cues. The challenge, then, is for the splicing machinery to recognize fairly short sections of exonic RNA embedded in very long stretches of intronic RNA (see poster, inset on BRCA1). It is common for human primary transcripts to be many times larger than the final mature mRNA after splicing. The majority of mature mRNAs are 2–4 kb, but primary transcripts can have many introns, each typically 0.5–10 kb, although shorter and longer ones are found frequently. Human genes challenge the splicing machinery with a seemingly insurmountable problem. Alternative splicing is a highly regulated process, and is recognized increasingly as a player in cancer development. Genes may produce several protein products by the use of alternative mRNA splicing, in which different exons and different intron/exon junctions may be alternatively used in different splice products from the same primary transcript. ![]() Additionally, in multicellular eukaryotes, most primary transcripts must undergo splicing reactions, in which exons are joined together and non-coding intervening sequences (introns) are removed (see poster). In the simplest cases, the primary transcript must acquire a 3′ poly-adenine tail and a 5′ methyl guanine cap in order to be transported to the cytoplasm, undergo translation, and remain stable long enough to produce a functional amount of protein. The steps between transcription and translation in eukaryotes are very complicated.
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