Up-regulation of the proapoptotic caspase 2 splicing isoform by a candidate tumor suppressor, RBM5.
Similar to many genes involved in programmed cell death (PCD), the caspase 2 (casp-2) gene generates both proapoptotic and antiapoptotic isoforms by alternative splicing. Using a yeast RNA-protein interaction assay, we identified RBM5 (also known as LUCA-15) as a protein that binds to casp-2 pre-mRNA. In both transfected cells and in vitro splicing assay, RBM5 enhances the formation of proapoptotic Casp-2L. RBM5 binds to a U/C-rich sequence immediately upstream of the previously identified In100 splicing repressor element. Our mutagenesis experiments demonstrate that RBM5 binding to this intronic sequence regulates the ratio of proapoptotic/antiapoptotic casp-2 splicing isoforms, suggesting that casp-2 splicing regulation by RBM5 may contribute to its tumor suppressor activity. Our work has uncovered a player in casp-2 alternative splicing regulation and revealed a link between the alternative splicing regulator and the candidate tumor suppressor gene. Together with previous studies, our work suggests that splicing control of cell death genes may be an important aspect in tumorigenesis. Enhancing the expression or activities of splicing regulators that promote the production of proapoptotic splicing isoforms might provide a therapeutic approach to cancer.
Fushimi
Kazuo
K
Department of Neurology, Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, 303 East Superior Street, Chicago, IL 60611, USA.
Ray
Payal
P
Kar
Amar
A
Wang
Lei
L
Sutherland
Leslie C
LC
Wu
Jane Y
JY
D017398:Alternative Splicing; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D001665:Binding Sites; D053143:Caspase 2 / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000209:etiology; D011485:Protein Binding; D020033:Protein Isoforms; D012322:RNA Precursors / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics*
D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D020033:Protein Isoforms; C473448:RBM5 protein, human; D012322:RNA Precursors; D016601:RNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C490360:CASP2 protein, human; D053143:Caspase 2; D003546:Cysteine Endopeptidases