Identification of Two RNA cis-Elements That Function to Regulate the 5′ Splice Site Selection of Bcl-x Pre-mRNA in Response to Ceramide

Massiello, Autumn; Salas, Arelis; Pinkerman, Ryan L.; Roddy, Patrick; Roesser, James R.; Chalfant, Charles E.

doi:10.1074/jbc.m313950200

Cited by 60 publications

(72 citation statements)

References 39 publications

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“…Chemotherapeutic agents induce a pro-apoptotic change in the alternative splicing of caspase 9 and Bcl-x pre-mRNA (Massiello et al, 2004). This effect is mediated by ceramide-dependent activation of PP1 (Massiello et al, 2004).…”

Section: Regulation Of Cell Survival By C1p and S1pmentioning

confidence: 99%

Sphingosine 1-phosphate and ceramide 1-phosphate: expanding roles in cell signaling

Chalfant

Spiegel

2005

Journal of Cell Science

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The phosphorylated sphingolipid metabolites sphingosine 1-phosphate (S1P) and ceramide 1-phosphate (C1P) have emerged as potent bioactive agents. Recent studies have begun to define new biological functions for these lipids. Generated by sphingosine kinases and ceramide kinase, they control numerous aspects of cell physiology, including cell survival and mammalian inflammatory responses. Interestingly, S1P is involved in cyclooxygenase-2 induction and C1P is required for the activation and translocation of cPLA2. This suggests that these two sphingolipid metabolites may act in concert to regulate production of eicosanoids, important inflammatory mediators. Whereas S1P functions mainly via G-protein-coupled receptors, C1P appears to bind directly to targets such as cPLA2 and protein phosphatase 1/2A. S1P probably also has intracellular targets, and in plants it appears to directly regulate the G protein α subunit GPA1.

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Section: Regulation Of Cell Survival By C1p and S1pmentioning

confidence: 99%

Sphingosine 1-phosphate and ceramide 1-phosphate: expanding roles in cell signaling

Chalfant

Spiegel

2005

Journal of Cell Science

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399

339

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“…The lipid ceramide can also cause the proapoptotic Bclx splicing switch. Ceramide inhibits PP1, which dephosphorylates the splicing factor ASF/SF2, and the splicing switch depends on an ASF/SF2 binding site near the BclXs splice site (96). The anticancer drug NB-506, on the other hand, is thought to function in part by inhibiting phosphorylation of ASF/SF2 (97).…”

Section: Alternative Splicing and Cancer Treatmentmentioning

confidence: 99%

Aberrant and Alternative Splicing in Cancer

2004

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Pre-mRNA splicing is a sophisticated and ubiquitous nuclear process, which is a natural source of cancer-causing errors in gene expression. Intronic splice site mutations of tumor suppressor genes often cause exon-skipping events that truncate proteins just like classical nonsense mutations. Also, many studies over the last 20 years have reported cancerspecific alternative splicing in the absence of genomic mutations. Affected proteins include transcription factors, cell signal transducers, and components of the extracellular matrix. Antibodies against alternatively spliced products on cancer cells are currently in clinical trials, and competitive reverse transcription-PCR across regions of alternative splicing is being used as a simple diagnostic test. As well as being associated with cancer, the nature of the alternative gene products is usually consistent with an active role in cancer; therefore, the alternative splicing process itself is a potential target for gene therapy. Splice Site Mutations Can Cause Aberrant Splicing and CancerDefects in mRNA splicing are an important cause of disease (1-3). The most common form of splicing defects are genomic splice site point mutations, and a recent survey found 29 different p53 splice site mutations in Ͼ12 different types of cancer (4). Ninety-nine percent of all exons are flanked by the intronic dinucleotides GT and AG at the 5Ј and 3Ј splice sites respectively, and mutation of these sites usually causes exclusion of the adjacent exon (Fig. 1A), although sometimes splice site mutations have even more drastic consequences, e.g., double exon skipping in MLH1 in hereditary nonpolyposis colorectal cancer (5). More than half of all exon deletions lead to truncation of the encoded protein and as such, mutations in tumor suppressor genes at the invariant intronic dinucleotide can act much as classical nonsense mutations. For example a GT to AT 5Ј splice site mutation in hSNF5 causes deletion of exon 7, a frame shift, and a truncated reading frame, and this causes infant brain tumors when a "second hit" is provided at the wild-type allele by a deletion (6). Similarly a 3Ј splice site AG to AT mutation caused constitutive loss of exon 4 of the APC gene in colorectal to liver metastases, where the wild-type allele was deleted (ref. 7; Fig. 1A).Mutations in the less conserved splice site consensus away from the invariant dinucleotides tend to lead to partial aberrant splicing, often with a relatively mild phenotype. For example, the most common pathogenic mutation of the ATM gene is linked to breast cancer but is incompletely penetrant and is thought to have originated in Palaeolithic times. This is a mutation at the sixth position of an intron that causes a proportion of transcripts to skip an exon and to be frame shifted leading to a truncated protein (8). The polypyrimidine tract signal associated with the 3Ј splice site is another hot spot for mutation (Fig. 1A). An intronic mutation 11 nucleotides upstream of a 3Ј splice site in MLH1 knocks out an exon, and this ...

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“…Bcl-x minigene (Bcl-x-g) was constructed following Massiello et al (Massiello et al, 2004). In brief, two fragments of Bcl-x genomic DNA were amplified by PCR and genomic DNA extracted from MCF-7 was used as a template.…”

Section: Minigene Construction and Rt-pcrmentioning

confidence: 99%

Loss of Pnn expression results in mouse early embryonic lethality and cellular apoptosis through SRSF1-mediated alternative expression of Bcl-xS and ICA**

Leu

Lin

et al. 2012

Journal of Cell Science

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SummaryPinin (Pnn), a serine/arginine-rich (SR)-related protein, has been shown to play multiple roles within eukaryotic cells including cell-cell adhesion, cell migration, regulation of gene transcription, mRNA export and alternative splicing. In this study, an attempt to generate mice homozygously deficient in Pnn failed because of early embryonic lethality. To evaluate the effects of loss of Pnn expression on cell survival, RNA interference experiments were performed in MCF-7 cells. Depletion of Pnn resulted in cellular apoptosis and nuclear condensation. In addition, nuclear speckles were disrupted, and expression levels of SR proteins were diminished. RT-PCR analysis showed that alternative splicing patterns of SRSF1 as well as of apoptosis-related genes Bcl-x and ICAD were altered, and expression levels of Bim isoforms were modulated in Pnn-depleted cells. Cellular apoptosis induced by Pnn depletion was rescued by overexpression of SRSF1, which also restored generation of Bcl-xL and functionless ICAD. Pnn expression is, therefore, essential for survival of mouse embryos and the breast carcinoma cell line MCF-7. Moreover, Pnn depletion, modulated by SRSF1, determines cellular apoptosis through activation of the expression of pro-apoptotic Bcl-xS transcripts.

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Identification of Two RNA cis-Elements That Function to Regulate the 5′ Splice Site Selection of Bcl-x Pre-mRNA in Response to Ceramide

Cited by 60 publications

References 39 publications

Sphingosine 1-phosphate and ceramide 1-phosphate: expanding roles in cell signaling

Sphingosine 1-phosphate and ceramide 1-phosphate: expanding roles in cell signaling

Aberrant and Alternative Splicing in Cancer

Loss of Pnn expression results in mouse early embryonic lethality and cellular apoptosis through SRSF1-mediated alternative expression of Bcl-xS and ICA**

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