Increased expression levels of the RNA splicing regulator Transformer2fl （abbreviated Tra2fl） have been reported in several types of cancer. Recent work has revealed an intimate cross-regulation between Tra2fl and t...Increased expression levels of the RNA splicing regulator Transformer2fl （abbreviated Tra2fl） have been reported in several types of cancer. Recent work has revealed an intimate cross-regulation between Tra2fl and the highly similar Tra2a protein in human breast cancer cells, though these two proteins are encoded by separate genes created by a gene duplication that occurred over 500 million years ago. This cross-regulation involves splicing control of a special class of exons, called poison exons. Down-regulation of Tra2fl reduces splicing inclu- sion of a poison exon in the mRNA encoding Tra2a, thereby up-regulating Tra2a protein expression. This buffers any splicing changes that might be caused by individual depletion of Tra2fl alone. Discovery of this cross-regulation pathway, and its by-pass by joint deple- tion of both human Tra2 proteins, revealed Tra2 proteins are essential for breast cancer cell viability, and led to the identification of important targets for splicing control. These exons include a critical exon within the checkpoint kinase 1 （CHK1） gene that plays a crucial function in the protection of cancer cells from replication stress. Breast cancer cells depleted for Tra2 proteins have reduced CHK1 protein levels and accumulate DNA damage. These data suggest Tra2 proteins and/or their splicing targets as possible cancer drug targets.展开更多
It is well known that many genes implicated in the development and progression of breast cancer undergo aberrant alternative splicing events to produce proteinswithpro-cancerproperties.These changes in alternative spl...It is well known that many genes implicated in the development and progression of breast cancer undergo aberrant alternative splicing events to produce proteinswithpro-cancerproperties.These changes in alternative splicingcan arise frommutations or single-nucleotide polymorphisms(SNPs)within the DNA sequences of cancer-related genes,which can strongly affect the activity of splicing factors and influence the splice site choice.However,it is important to note that absence of mutations is not sufficient to prevent misleading choices in splice site selection.There is nowincreasing evidence to demonstrate that the expression profile of ten splicing factors(including SRs and hnRNPs)and eight RNA-binding proteins changes in breast cancer cells compared with normal cells.These modifications strongly influence the alternative splicing pattern of many cancer-related genes despite the absence of any detrimental mutations within their DNA sequences.Thus,a comprehensive assessment of the splicing factor status in breast cancer is important to provide insights into the mechanisms that lead to breast cancer development and metastasis.Whilst most studies focus on mutations that affect alternative splicing in cancer-related genes,this review focuses on splicing factors and RNA-binding proteins that are themselves deregulated in breast cancer and implicated in cancer-related alternative splicing events.展开更多
文摘Increased expression levels of the RNA splicing regulator Transformer2fl （abbreviated Tra2fl） have been reported in several types of cancer. Recent work has revealed an intimate cross-regulation between Tra2fl and the highly similar Tra2a protein in human breast cancer cells, though these two proteins are encoded by separate genes created by a gene duplication that occurred over 500 million years ago. This cross-regulation involves splicing control of a special class of exons, called poison exons. Down-regulation of Tra2fl reduces splicing inclu- sion of a poison exon in the mRNA encoding Tra2a, thereby up-regulating Tra2a protein expression. This buffers any splicing changes that might be caused by individual depletion of Tra2fl alone. Discovery of this cross-regulation pathway, and its by-pass by joint deple- tion of both human Tra2 proteins, revealed Tra2 proteins are essential for breast cancer cell viability, and led to the identification of important targets for splicing control. These exons include a critical exon within the checkpoint kinase 1 （CHK1） gene that plays a crucial function in the protection of cancer cells from replication stress. Breast cancer cells depleted for Tra2 proteins have reduced CHK1 protein levels and accumulate DNA damage. These data suggest Tra2 proteins and/or their splicing targets as possible cancer drug targets.
基金This work was supported by the Royal Victoria Infirmary Breast Cancer Appeal(Reference number BH136312).
文摘It is well known that many genes implicated in the development and progression of breast cancer undergo aberrant alternative splicing events to produce proteinswithpro-cancerproperties.These changes in alternative splicingcan arise frommutations or single-nucleotide polymorphisms(SNPs)within the DNA sequences of cancer-related genes,which can strongly affect the activity of splicing factors and influence the splice site choice.However,it is important to note that absence of mutations is not sufficient to prevent misleading choices in splice site selection.There is nowincreasing evidence to demonstrate that the expression profile of ten splicing factors(including SRs and hnRNPs)and eight RNA-binding proteins changes in breast cancer cells compared with normal cells.These modifications strongly influence the alternative splicing pattern of many cancer-related genes despite the absence of any detrimental mutations within their DNA sequences.Thus,a comprehensive assessment of the splicing factor status in breast cancer is important to provide insights into the mechanisms that lead to breast cancer development and metastasis.Whilst most studies focus on mutations that affect alternative splicing in cancer-related genes,this review focuses on splicing factors and RNA-binding proteins that are themselves deregulated in breast cancer and implicated in cancer-related alternative splicing events.
