The connection between splicing and cancer

Abstract

The response of cells to environmental signals, as well as their differentiation, death or malignant transformation, involves changes in gene expression. For many years, the modulation of gene expression was thought to be restricted to, or at least dominated by, the control of transcription. According to the Jacob-Monod-Lwoff paradigm, established in bacteria and logically extended to eukaryotes, what made a cell a cell was the combinatorial turning on and off of genes. The discovery of introns and the process of splicing, which eliminates them from the precursor mRNA, introduced an exciting but also perturbing factor in our simplified conceptions of the flow of gene expression in eukaryotes. Introns must be excised precisely to generate bona fide mRNA molecules; otherwise, translational frame shifts would be introduced. Introns are much longer than exons and most of their nucleotide sequence seems to be irrelevant except for the 'donor' and 'acceptor' consensus sequences located at their extremities, and the branching sequence that precedes the acceptor sequence. The spliceosome, a sophisticated nuclear machine comprising five types of small nuclear ribonucleoprotein (snRNP) and hundreds of auxiliary proteins, takes care of intron excision and exon joining repeatedly at each and every one of the seven splicing events that occur on average per human pre-mRNA molecule (Lander et al., 2001).'What is all this for?', a teleologist might ask. We know now that the high adaptive value of introns resides in the fact that they permitted exon shuffling in the past and alternative splicing in the present (Sharp, 1994). However, the apparent 'irrationality of introns' (I. Eperon, http://www.eurasnet.info/ ian_eperon.shtml) was questioned early on following the discovery that mutations that affect splicing, quantitatively or qualitatively, are a widespread source of hereditary diseases. No matter how absurd or energy consuming a biological process appears to be, if its disruption or perturbation causes disease, it must be important, and its conservation in evolution is paramount. The links between splicing and human disease have been extensively reviewed lately (Caceres and Kornblihtt, 2002;Cartegni et al., 2002;Faustino and Cooper, 2003;Pagani and Baralle, 2004). The specific association between splicing and cancer has received less attention (Brinkman, 2004;Venables, 2006), perhaps because the field is still emerging. Here we examine this connection, focusing not only on mutations in cis-acting splicing sequences that are associated with cancer but also on the variations in normal splicing processes and the signals that may affect them in cancer cells. The basic language of splicingSplice sites, branch sites, splicing enhancers and splicing silencers Splicing occurs when a group of proteins and RNPs recognize specific RNA sequences conserved at the boundaries of introns (Fig. 1A). The classical spliceosome, which acts on >99% of introns from genes transcribed by RNA polymerase II (Pol II), recognizes a 5Ј donor splice site...

Attenuation of proteolysis‐mediated cyclin E regulation by alternatively spliced Parkin in human colorectal cancers

“…34 Indeed, many cancerspecific isoforms of tumor-related genes produced by alternative splicing have been identified in several human tumors. 34,35 The most studied alternatively spliced gene in cancers might be CD44, in which inclusion of variable exons correlates with tumor development and metastasis. 36 It was shown that phosphorylation of the nuclear RNA binding protein Sam68 activated by growth signaling regulates alternative splicing of variable exon 5 of the CD44 gene in lymphoma cells.…”

Genetic sequence variations of BRCA1-interacting genes AURKA, BAP1, BARD1 and DHX9 in French Canadian Families with high risk of breast cancer

“…The goal of this study being the identification of deleterious mutation, and given that such deleterious disease-causing mutations producing a premature truncation of the protein occur mostly within the coding region, complementary DNA (cDNA) mutation screening was therefore performed. In addition, since alternative splicing is now recognized as the primary source of human proteomic diversity and gene regulation and that an increasing number of disease-causing mutations affecting the correct splicing of genes are identified, 48 cDNA material definitively represents a resource of choice as alternative splice forms could not be detected when extensive re-sequencing is performed on genomic DNA.…”

Alternative splicing of G protein-coupled receptors: physiology and pathophysiology

“…A large number of molecular changes, including genetic instability, insufficient DNA mismatch repair, increased oncogene expression and defects in several splicing mechanisms F o r R e v i e w O n l y have been described in cancer cells relative to their healthy counterparts [7,117].…”

“…muscular dystrophy, cystic fibrosis, asthma, insulin-dependent (type I) diabetes, cancer [6]). In addition, mutations that lead to alterations in the splicing of various proteins, including G protein-coupled receptors (GPCRs), have been identified in a variety of cancers, including melanomas, breast, ovarian, prostate, liver and gastrointestinal cancers [7,8,9]. GPCRs constitute the largest family of membrane-associated receptors.…”