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Modulation of alternative splicing by anticancer drugs

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Pre‐mRNA alternative splicing is a highly regulated process that generates multiple mRNAs coding different protein isoforms. These protein isoforms may have similar, different, or even opposing functions. Expression of genes involved in cell growth and apoptosis are often altered in cancer cells. Studying the alternative splicing patterns of these important genes can have a significant role in the treatment of cancer. Resistance to chemotherapy is often caused due to overexpression of anti‐apoptotic isoforms or suppression of pro‐apoptotic isoforms. Anticancer drugs are capable of modulating the expression of different transcript isoforms of genes. Some anticancer drugs induce pro‐apoptotic transcript isoforms leading to apoptosis or at least sensitizing cells to chemotherapy. However, in other cases, they shift the splicing toward isoforms having anti‐apoptotic functions thus conferring resistance to chemotherapy. This mini‐review summarizes the current knowledge about alternative splicing of some important genes involved in cancers. Furthermore, splicing patterns as well as generation of functionally distinct protein isoforms have also been mentioned. Role of various anticancer drugs in modulating alternative splicing of these genes has been reported along with a brief insight into their mechanism of action. Modulation of alternative splicing toward production of pro‐apoptotic isoforms of various genes by anticancer drugs offers great therapeutic potential in the treatment of cancer. WIREs RNA 2015, 6:369–379. doi: 10.1002/wrna.1283

Alternative splicing in Bcl‐x and caspase‐2. (a) Alternative splicing of Bcl‐x pre‐mRNA. Splicing at the downstream or upstream 5′ alternative of splice site at exon 2 of Bcl‐x produces two different isoforms coding for proteins having opposing functions. Products coded by Bcl‐xL are anti‐apoptotic, whereas Bcl‐xS functions as pro‐apoptotic protein. (b) Inclusion of exon 9 into caspase‐2 mRNA. Inclusion of exon 9 into caspase‐2 mRNA is inhibited by an intronic sequence. Inclusion of exon 9 leads to premature introduction of stop codon in exon 10 leading to production of shorter caspase‐2 isoform (Casp2S). Exclusion of exon 9 leads to production of long isoform of caspase‐2 (Casp2L).
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Mechanism of modulation of alternative splicing by various drugs. PP1‐dependent mechanism. Various anticancer drugs were found to modulate the alternative splicing of various genes through PP1. PP1 dephosphorylates SR protein. In some cases, endogenous ceramide was found to mediate the effect of anticancer drugs in controlling the phosphorylation state of PP1.
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Domains and alternatively spliced variants of mdm2. (a) MDM2 contains four major domains that include p53 binding domain and ring finger domain located at N‐terminal and C‐terminal, respectively. Two other regions are located in the middle that include acidic region and Zn finger region, which are responsible for providing binding sites for important regulatory factors. (b) Alternative splicing of mdm2 gene produces two major splice variants that arise due to exon skipping. Of the 12 total exons, exons 4–9 and 4–11 are skipped to form smaller transcript variants, namely mdm2A and mdm2B, respectively.
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Alternative splicing in caspase‐9 and Apaf‐1. (a) Functionally distinct isoforms of caspase‐9 produced by alternative splicing. Alternative splicing of caspase‐9 pre‐mRNA produces two different isoforms, caspase‐9a and caspase‐9b, where a four‐exon cassette, that includes exons 3–6, is skipped to produce shorter variant caspase‐9b. Full‐length caspase‐9a encodes for a pro‐apoptotic protein, while the shorter variant codes for protein responsible for cell survival. (b) Alternatively spliced variants of Apaf 1. Exon 18 is either skipped or retained in mature Apaf 1 mRNA to produce two different isoforms. Skipping of exon 18 renders protein unable to bind and activate caspase‐9. However, retention of exon 18 in mature transcript codes for a protein capable of activating caspase‐9.
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RNA in Disease and Development > RNA in Disease
RNA Processing
RNA Processing > Splicing Regulation/Alternative Splicing

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