Modification of alternative splicing pathways as a potential approach to chemotherapy

Mercatante, Danielle R.; Kole, Ryszard

doi:10.1016/s0163-7258(99)00067-4

Cited by 69 publications

(50 citation statements)

References 44 publications

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“…Production of alternative transcripts may be a consequence of disease such as cancer (Mercatante and Kole, 2000). These findings seem to be in accordance with the presence of PRMT1-v4 splice variant in colon tissue (normal and cancerous) but not in breast tissue (our unpublished data).…”

Section: Discussionsupporting

confidence: 85%

The PRMT1 gene expression pattern in colon cancer

et al. 2008

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The methylation of arginine has been implicated in many cellular processes, such as regulation of transcription, mRNA splicing, RNA metabolism and transport. The enzymes responsible for this modification are the protein arginine methyltransferases. The most abundant methyltransferase in human cells is protein arginine methyltransferase 1. Methylation processes appear to interfere in the emergence of several diseases, including cancer. During our study, we examined the expression pattern of protein arginine methyltransferase 1 gene in colon cancer patients. The emerging results showed that the expression of one of the gene variants is associated with statistical significant probability to clinical and histological parameters, such as nodal status and stage. This is a first attempt to acquire an insight on the possible relation of the expression pattern of protein arginine methyltransferase 1 and colon cancer progression.

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Section: Discussionsupporting

confidence: 85%

The PRMT1 gene expression pattern in colon cancer

et al. 2008

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“…34,35 However, the molecular mechanisms involved in such processes remain largely unknown. Importantly, and consistent with a function of SR proteins during the response to DNA damage, it has been previously shown that SC35 accumulates following g-irradiation.…”

Section: Discussionmentioning

confidence: 99%

E2F1 controls alternative splicing pattern of genes involved in apoptosis through upregulation of the splicing factor SC35

et al. 2008

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The transcription factor E2F1 has a key function during S phase progression and apoptosis. It has been well-demonstrated that the apoptotic function of E2F1 involves its ability to transactivate pro-apoptotic target genes. Alternative splicing of pre-mRNAs also has an important function in the regulation of apoptosis. In this study, we identify the splicing factor SC35, a member of the SerRich Arg (SR) proteins family, as a new transcriptional target of E2F1. We demonstrate that E2F1 requires SC35 to switch the alternative splicing profile of various apoptotic genes such as c-flip, caspases-8 and -9 and Bcl-x, towards the expression of pro-apoptotic splice variants. Finally, we provide evidence that E2F1 upregulates SC35 in response to DNA-damaging agents and show that SC35 is required for apoptosis in response to these drugs. Taken together, these results demonstrate that E2F1 controls pre-mRNA processing events to induce apoptosis and identify the SC35 SR protein as a key direct E2F1-target in this setting. Cell Death and Differentiation (2008) 15, 1815-1823 doi:10.1038/cdd.2008 published online 19 September 2008 Pre-mRNA splicing is an essential step for the expression of most genes in higher eukaryotic cells. This process has emerged as an important mechanism of genetic diversity as about 74% of human genes undergo alternative splicing, leading to the production of various protein isoforms. 1 SC35 belongs to the serine/arginine-rich (SR) protein family, one of the most important class of splicing regulators. Members of the SR family have a modular structure consisting of one or two copies of an N-terminal RRM (RNA-recognition motif) followed by a C terminus rich in serine and arginine residues known as the RS domain. They act at multiple steps of spliceosome assembly and participate in both constitutive and alternative splicing. 2 Together with most of the other splicing factors, SR proteins localize to nuclear subregions termed nuclear speckles. 3 Extensive serine phosphorylation of the RS domain has an important function in the regulation of both the localization and the activities of SR proteins. 4 Although the splicing functions of SR proteins have been well documented in vitro, their roles and physiological targets in vivo are less well known. However, based on gene targeting experiments demonstrating that they are required for cell viability and/or animal development, SR proteins undoubtedly control essential biological functions.Apoptosis is one of the cellular processes in which alternative splicing has an important regulatory function. Indeed, a remarkable number of transcripts that encode proteins involved in the apoptotic pathway are subjected to alternative splicing. This usually drives the expression of proteins with opposite functions, either pro-or anti-apoptotic. 5 Interestingly, changes in SR protein phosphorylation have been observed upon apoptotic stimulation following activation of the Fas receptor. 6 In addition, in vitro overexpression experiments have suggested a potential role for ...

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“…21 However, the results of the alterations in the expression of these splicing factors during cancer progression and/or metastasis are not known. Because a number of genes have been characterized to be alternately spliced in cancer, 22 it is very likely that alterations in the splicing of key genes is the result of alterations in splicing factors.…”

Section: Discussionmentioning

confidence: 99%

Human SPF45, a Splicing Factor, Has Limited Expression in Normal Tissues, Is Overexpressed in Many Tumors, and Can Confer a Multidrug-Resistant Phenotype to Cells

Sampath

Long

Shepard

et al. 2003

The American Journal of Pathology

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Our effort to identify novel drug-resistant genes in cyclophosphamide-resistant EMT6 mouse mammary tumors led us to the identification of SPF45. Simultaneously, other groups identified SPF45 as a component of the spliceosome that is involved in alternative splicing. We isolated the human homologue and examined the normal human tissue expression, tumor expression, and the phenotype caused by overexpression of human SPF45. Our analyses revealed that SPF45 is expressed in many, but not all, normal tissues tested with predominant expression in normal ductal epithelial cells of the breast, liver, pancreas, and prostate. Our analyses using tissue microarrays and sausages of tumors indicated that SPF45 is highly expressed in numerous carcinomas including bladder, breast, colon, lung, ovarian, pancreatic, and prostate. Interestingly, this study revealed that overexpression of SPF45 in HeLa, a cervical carcinoma cell line, resulted in drug resistance to doxorubicin and vincristine, two chemotherapeutic drugs commonly used in cancer. To our knowledge, this is the first study showing tumor overexpression of an alternate splicing factor resulting in drug resistance. The development of multidrug resistance is a major hurdle in the treatment of cancer. Although some genes that confer multidrug resistance are known, it is clear that many other genes remain to be identified. The characterization of novel mechanisms that lead to drug resistance would enable the development of a targeted new generation of anti-cancer drugs. To identify novel genes involved in drug resistance we performed suppressivesubtractive polymerase chain reaction analyses of the cyclophosphamide-resistant EMT6 mouse mammary tumor cells and the parental EMT6 tumors. This led to the identification of a gene that was highly homologous to a DNA damage response protein, DRT111 of Arabidopsis (unpublished observations). 1 While this work was in progress, Neubauer and colleagues, 1 identified a novel protein from the spliceosome. An analysis of all proteins present in the spliceosomal complex led to the identification of 25 previously identified proteins and 20 novel proteins. One of the novel proteins thus identified was named SPF45 (splicing factor 45 kd). This protein was identical to the one that was identified by our suppressive-subtractive polymerase chain reaction analysis. Neubauer and colleagues, 1 further showed that SPF45 was a nuclear protein that co-localizes with U1A snRNP in nuclear speckles, a known reservoir of splicing factors. [2][3][4] Recently Rappsilber and colleagues, 5 have described the identification of 311 proteins in the human spliceosomal complex of which 96 were novel proteins. Again, in this study, SPF45 was identified as a component of the spliceosome.Lallena and colleagues, 6 demonstrated that SPF45 regulates the alternate splicing of the Drosophila sexlethal gene (sxl). SXL protein is expressed only in female flies, but not in males. 7 Exon3 of Sxl plays a very important role in determining the expression of SXL because its inclus...

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Modification of alternative splicing pathways as a potential approach to chemotherapy

Cited by 69 publications

References 44 publications

The PRMT1 gene expression pattern in colon cancer

The PRMT1 gene expression pattern in colon cancer

E2F1 controls alternative splicing pattern of genes involved in apoptosis through upregulation of the splicing factor SC35

Human SPF45, a Splicing Factor, Has Limited Expression in Normal Tissues, Is Overexpressed in Many Tumors, and Can Confer a Multidrug-Resistant Phenotype to Cells

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