RESUMEN
Alternative splicing is the key to human gene expression regulation and plays a decisive role in enlarging the diversity of functional proteins. Alternative splicing is an important biomarker in tumor progression, which is closely related to the development of tumors. Tumor cells tend to produce alternative spliceosome that are conducive to their progression. Therefore, targeting regulation of tumor-specific alternative spliceosomes is a potential strategy for tumor therapy. Herein, we provide a brief review of the complex relationship between alternative splicing and tumors. Alternative splicing works by removing non-coding sequences of pre-mRNA and assembling protein-coding fragments in different combinations, ultimately producing proteins with different or even opposite functions. Alternative splicing events can promote the transformation of tumor cells through apoptosis, invasion, metastasis, angiogenesis, and metabolism; they can also influence the effectiveness of cancer immunotherapy by affecting genes that play a key role in the immune pathway. We proposed that direct or indirect targeting of alternative splicing factors and oligonucleotide-based therapies are the main strategies to reverse tumor alternative splicing events. These findings will help us to better understand tumor-related alternative splicing and to develop new strategies for tumor treatment.
RESUMEN
Alternative splicing of pre-messenger RNA (pre-mRNA) is a crucial mechanism for the diversity of the human transcriptome and proteome. Alternative splicing is a complex gene regulation process. Whole-transcriptome analysis shows that 95% of human exonic genes are alternatively spliced, involving various cis-acting elements and trans-acting factors. Any changes in any component or step may cause erroneous splicing events and lead to the occurrence of various related diseases. In addition to gene replacement therapy that directly changes the splicing results, RNA splicing modification is expected to become a new therapeutic strategy to alleviate or treat diseases by targeting and correcting abnormal pre-mRNA splicing. Splicing modification tools currently developed including RNA trans-splicing, antisense oligonucleotides, small interfering RNA, and small molecule drugs can correct abnormal splicing through different ways. This article reviews the resent progress of epigenetic regulation of pre-mRNA alternative splicing in recent years, and discusses the occurrence and regulation of alternative splicing, the types of diseases caused by related splicing defects, and the current-used tools for targeting and altering splicing. The importance of splicing modification strategies in the future treatment of human diseases is envisioned.
RESUMEN
Retinitis pigmentosa (RP) is a large group of common hereditary eye diseases with highlyheterogeneous genetic background. Over forty genes with diverse functionalities are associated with RP and they include a set of ubiquitously expressed genes. These include five genes involved in the precursor messenger RNA( premRNA) splicing. Recent progress in disease gene identification for RP has established the involvement of pre-mRNA splicing as one important mechanism in the disease etiology and has shed light on the splicing process itself, a fundamental biological process. To this date, studies in this field have been focused on two major issues. First, how do the mutations of the adRP associated splicing factors (adRP-SF) affect the splicing function? Second, how do the mutations in these ubiquitously expressed genes lead to specific retinopathy? The two topics fit with the two continuous important steps of the disease pathogenesis. Recently, researchers have made a dramatic progress in the first topic. The identification of the SNRNP200 gene,the fifth adRP-SF and its relevant functional study has shown significance to the progress in the study of RP. Numerous investigations are also being carried out in addressing the second issue.Generation of a variety of models led to a better description of the pathological process of the disease. However, in respect to the key pathogenic mechanism,researchers are still puzzled with a number of confusing questions. In this commentary,the results from the latest investigations were summarized, and in particular,the difficulties in studying the molecular mechanism by which the pre-mRNA splicing deficiency causes RP were detailed.
RESUMEN
SR proteins play important roles in regulating alternative pre-mRNA splicing. As a newly discovered neural and reproductive tissue specific SR protein, SRp38 regulates the alternative splicing of several genes important for neural function, such as GluR-B, Trk-C and NCAML1. It also acts as a splicing inhibitor during mitosis or stress response in order to prevent wrong splicing. The expression of SRp38 in mouse retina was investigated by Western blot and immunohistochemistry (IHC) analyses. The result shows that the expression of SRp38 proteins in mouse retina is region-specific, with extensive distribution in the outer and inner plexiform layers, inner nuclear layer and ganglion cell layer, but no expression in outer nuclear layer. Double staining of isolated retina cells with anti-SRp38 and anti-Trk-C antibodies showed that SRp38 is localized in the dendrites, somata and axon terminals of rod-bipolar cells. By transient co-transmission of over-expressed SRp38 plasmid and RT-PCR analyses, the further results showed that overexpressed SRp38 could promote the splicing of the Flip isoform of GluR-B minegene in R28 cells. The result suggests that SRp38 may play important roles in the retinal function, possibly via regulating the neural-specific alternative splicing of genes as GluR-B.
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Gliomas constitute the most common type of primary brain tumor. Alternative pre-mRNA splicing may play roles in the carcinogenesis, cell growth and invasion in various types of gliomas. Factors regulating the alternative spicing in gliomas include cis-regulatory element (for example, ESE, ISS and ESS) and trans-regulatory factors (such as SRp55, SC35, SF2/ASF and PTB). Recent progresses demonstrate that many genes associated with gliomas, including those encoding tumor suppressors or promoters, enzymes, receptors and ion channels are subject to regulation by alternative pre-mRNA splicing. Therefore, studying the alternative pre-mRNA splicing in gliomas will be of benefit to understanding the molecular basis of gliomas and identifying new targets potentially useful for early diagnose as well as therapy of gliomas.
RESUMEN
Objective:To prepare specific antibody against the pre mRNA splicing protein Tra2? in human fetal tissues.Methods:A specific antigen fragment of human Tra2? was cloned into the pGEX 3x expression vector to express a recombinant GST Tra2? fusion protein.The fusion protein was expressed,purified and used as an antigen to immunize the New Zealand rabbit,and the polyclonal antibody to Tra2? was obtained.Results:The antibody was successfully used to detect Tra2? protein in human fetal cerebrum with Western blot and immunohistochemistry analysis.Conclusion:This prepard antibody has good specificity and can be used to detect the Tra2? protein in the human fetal tissues.