== Cis-acting sequences required for the splicing reaction and different types of option splicing events.(A)Splicing consensus sequences of a typical eukaryotic gene (exon/intron splice site signals, branch site and polypyrimidine tract).(B)Alternatively spliced mRNAs result from exon skipping, intron retention, usage of option 3- (acceptor) or 5- (donor) sites and from selection of mutually exclusive exons. stopped growing in parallel with the complexity of the proteome. Thus, the human genome contains only 20.000 – 25.000 genes (International Human Genome Sequencing Consortium 2004 SJFδ [1]), a number not significantly different from that counted in less complex organisms such as sea urchin (23,000) (Sea Urchin Genome Sequencing Consortium 2006) and the nematode worm (19,000) [2]. Moreover, the number of human genes is not sufficient to account for all the proteins revealed by proteomic analysis. How can these paradoxes be explained? Recent cDNA sequencing and microarray SJFδ data have implicatedalternativesplicing (AS) as the main source of proteomic and functional diversity in metazoan organisms [3]. Together with option promoters and polyadenylation sites, RNA editing and post-translational processing, AS gives rise to an estimated number of at least 100,000 different human proteins. The term alternative splicing explains any situation in which a single primary transcript (pre-mRNA) can be spliced in more than one pattern to generate multiple, distinct mature mRNAs leading to expression of protein isoforms with different structural and functional properties. The “record-holder” for alternative splicing is usually a Drosophila gene calledDscam, with 38,000 splice variants, more than the number of Drosophila genes [4]. In humans at least 70% (and this proportion might be even higher!!) of the genes encode for transcripts that undergo option splicing [5], which underscores the importance of this regulatory mechanism in the biology of our species. Because of its capacity to generate protein diversity, alternative splicing is expected to play a major role in gene expression regulation, a prediction which is usually substantiated by the observation that appropriate spatio-temporal generation of splicing variants is involved in many cellular and developmental processes (including sex determination, apoptosis, axon Rabbit Polyclonal to Ik3-2 guidance, cell excitation and contraction and many others). It is not surprising, therefore, that deregulation of option splicing programs is usually tightly linked to inherited and acquired human genetic disorders [6]. Indeed, works in the last few years have started to recognize inappropriate option splicing as a genetic modifier during tumorigenesis [7]. SJFδ Many cancer-related genes are regulated by option splicing. They encode for proteins involved in all major aspects of cancer cell biology, including cell cycle control, proliferation, differentiation, signal transduction pathways, cell death, angiogenesis, invasion, motility and metastasis [8]. A common SJFδ signature of cancer cells is a general loss of splicing fidelity, with the concomitant reorganization of splicing profiles, and even switching to specific splicing isoforms usually expressed in other cell types. All these events may contribute to carcinogenesis [8]. Notably, there are several cases of option splicing that are restricted to specific cancer types, which clearly involves that particular splicing isoform in tumor progression [8,9]. SJFδ Cancer-specific splicing events may be also beneficial to therapy, since they generate novel epitopes against which it is possible to raise antibodies for immunotherapy. Hence, there is great interest in discovering the effect of option splicing around the transcriptome complexity in cancer cells and in understanding how this regulatory mechanism contributes to tumorigenesis. This review discusses (1) the basic mechanisms of alternative splicing, (2) the present knowledge around the regulatory mechanisms governing alternative splicing and their deregulation in cancer, (3) the biological consequences deriving.