Alternative splicing and breast cancer

Dutertre, Martin; Vagner, Stéphan; Auboeuf, Didier

doi:10.4161/rna.7.4.12152

Cited by 37 publications

(37 citation statements)

References 119 publications

(186 reference statements)

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“…Increasing evidences indicate that alterations of splicing programs contribute to tumor progression (Blencowe, 2003;David and Manley, 2010;Warzecha et al, 2010;Dutertre et al, 2010b). Indeed, most of the human genes can generate different splicing variants coding for different protein isoforms having slightly different activities or even opposite biological activities (Stamm et al, 2005;David and Manley, 2010;Dutertre et al, 2010b).…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, most of the human genes can generate different splicing variants coding for different protein isoforms having slightly different activities or even opposite biological activities (Stamm et al, 2005;David and Manley, 2010;Dutertre et al, 2010b). In addition, alternative splicing can have an important role in the regulation of gene expression level.…”

Section: Introductionmentioning

confidence: 99%

“…Although transcriptional programs are under the control of transcriptional factors and coregulators, splicing programs are under the control of splicing factors (Blencowe, 2003;David and Manley, 2010;Warzecha et al, 2010;Dutertre et al, 2010b). An increasing number of proteins have been involved in both transcription and splicing (Auboeuf et al, 2007;Allemand et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Dual role of the ddx5/ddx17 RNA helicases in the control of the pro-migratory NFAT5 transcription factor

et al. 2012

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Ddx5 and ddx17 are two highly related RNA helicases involved in both transcription and splicing. These proteins coactivate transcription factors involved in cancer such as the estrogen receptor alpha, p53 and beta-catenin. Ddx5 and ddx17 are part of the splicing machinery and can modulate alternative splicing, the main mechanism increasing the proteome diversity. Alternative splicing also has a role in gene expression level regulation when it is coupled to the nonsensemediated mRNA decay (NMD) pathway. In this work, we report that ddx5 and ddx17 have a dual role in the control of the pro-migratory NFAT5 transcription factor. First, ddx5 and ddx17 act as transcriptional coactivators of NFAT5 and are required for activating NFAT5 target genes involved in tumor cell migration. Second, at the splicing level, ddx5 and ddx17 increase the inclusion of NFAT5 exon 5. As exon 5 contains a pre-mature translation termination codon, its inclusion leads to the regulation of NFAT5 mRNAs by the NMD pathway and to a decrease in NFAT5 protein level. Therefore, we demonstrated for the first time that a transcriptional coregulator can simultaneously regulate the transcriptional activity and alternative splicing of a transcription factor. This dual regulation, where ddx5 and ddx17 enhance the transcriptional activity of NFAT5 although reducing its protein expression level, suggests a critical role for ddx5 and ddx17 in tumor cell migration through the fine regulation of NFAT5 pathway.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dual role of the ddx5/ddx17 RNA helicases in the control of the pro-migratory NFAT5 transcription factor

et al. 2012

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“…Indeed, recent studies suggest a coordinated regulation of AS events playing a role in tissue differentiation, tumor progression, and in specific cellular programs. 1,2 A major aspect of a cell's life is dealing with a variety of biochemical and physical factors that challenge its integrity and homeostasis, thus generating a cellular stress. Such factors are called stress inducers.…”

Section: Introductionmentioning

confidence: 99%

The emerging role of pre-messenger RNA splicing in stress responses: Sending alternative messages and silent messengers

Dutertre¹,

Sanchez²,

Barbier³

et al. 2011

RNA Biology

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A lternative splicing (AS) of premessenger RNAs is a major process contributing to both transcriptome and proteome diversity in various physiological and pathological situations. There is also accumulating evidence that various stresses impact on AS. In particular, recent analyses of the transcriptome reveal large numbers of AS events that are regulated by genotoxic stress inducers like radiations and chemotherapeutic agents. Many AS events have the potential to affect the relative production of protein isoforms with different activities, as shown in the case of several genes involved in apoptosis. There is also increasing evidence that stresses induce "non-productive" splice variants, leading to a decrease in gene expression levels or preventing increases in protein levels despite transcriptional stimulation. This is typically achieved by the production of splice variants that are subject to nonsense-mediated decay. In addition, recent studies suggest that pre-mRNA splicing efficiency or fidelity may be altered by stresses. For example, various genotoxic agents induce multiple exon skipping in MDM2 transcripts, thereby preventing the production of the main p53-ubiquitin ligase and favoring p53 activity in response to genotoxic agents. In terms of mechanisms, stresses can impact on pre-mRNA splicing by inducing post-translational modifications and subcellular redistribution of splicing factors, or by targeting the communication between the splicing and transcription

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“…Among these defects, alternative splicing misregulation seems to be an important factor. Misregulation of alternative splicing can be observed in cancer cells in the absence of genomic mutations of the genes concerned (1). In cancer cells, aberrant alternative splicing can give rise to variants that are specifically expressed in cancer tissues and completely absent from normal ones (2).…”

Section: Introductionmentioning

confidence: 99%

Survivin-3B Potentiates Immune Escape in Cancer but Also Inhibits the Toxicity of Cancer Chemotherapy

et al. 2013

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Dysregulation in patterns of alternative RNA splicing in cancer cells is emerging as a significant factor in cancer pathophysiology. In this study, we investigated the little known alternative splice isoform survivin-3B (S-3B) that is overexpressed in a tumor-specific manner. Ectopic overexpression of S-3B drove tumorigenesis by facilitating immune escape in a manner associated with resistance to immune cell toxicity. This resistance was mediated by interaction of S-3B with procaspase-8, inhibiting death-inducing signaling complex formation in response to Fas/ Fas ligand interaction. We found that S-3B overexpression also mediated resistance to cancer chemotherapy, in this case through interactions with procaspase-6. S-3B binding to procaspase-6 inhibited its activation despite mitochondrial depolarization and caspase-3 activation. When combined with chemotherapy, S-3B targeting in vivo elicited a nearly eradication of tumors. Mechanistic investigations identified a previously unrecognized 7-amino acid region as responsible for the procancerous properties of survivin proteins. Taken together, our results defined S-3B as an important functional actor in tumor formation and treatment resistance. Cancer Res; 73(17); 5391-401. Ó2013 AACR.

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Alternative splicing and breast cancer

Cited by 37 publications

References 119 publications

Dual role of the ddx5/ddx17 RNA helicases in the control of the pro-migratory NFAT5 transcription factor

Dual role of the ddx5/ddx17 RNA helicases in the control of the pro-migratory NFAT5 transcription factor

The emerging role of pre-messenger RNA splicing in stress responses: Sending alternative messages and silent messengers

Survivin-3B Potentiates Immune Escape in Cancer but Also Inhibits the Toxicity of Cancer Chemotherapy

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