Abstract
Exon 2 of the Bcl-x gene undergoes alternative splicing in which the Bcl-xS splice variant promotes apoptosis in contrast to the anti-apoptotic splice variant Bcl-xL. In this study, the regulation of the alternative splicing of pre-mRNA of Bcl-x was examined in response to emetine. Treatment of different types of cancer cells with emetine dihydrochloride downregulated the level of Bcl-xL mRNA with a concomitant increase in the mRNA level of Bcl-xS in a dose- and time-dependent manner. Pretreatment with calyculin A, an inhibitor of protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A), blocked emetine-induced alternative splicing in contrast to okadaic acid, a specific inhibitor of PP2A in cells, demonstrating a PP1-mediated mechanism. Our finding on the regulation of RNA splicing of members of the Bcl-2 family in response to emetine presents a potential target for cancer treatment.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Alternative Splicing / drug effects*
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Cell Line, Tumor
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Cycloheximide / pharmacology
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Down-Regulation / drug effects
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Down-Regulation / genetics
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Emetine / pharmacology*
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Enzyme Inhibitors / pharmacology
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Female
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology
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Male
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Marine Toxins
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Okadaic Acid / pharmacology
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Oxazoles / pharmacology
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Prostatic Neoplasms / genetics
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / pathology
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Protein Phosphatase 1 / antagonists & inhibitors
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Protein Phosphatase 1 / metabolism*
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Protein Phosphatase 2 / antagonists & inhibitors
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Protein Phosphatase 2 / metabolism
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Up-Regulation / drug effects
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Up-Regulation / genetics
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Uterine Cervical Neoplasms / genetics
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Uterine Cervical Neoplasms / metabolism
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Uterine Cervical Neoplasms / pathology
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bcl-X Protein / genetics*
Substances
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BCL2L1 protein, human
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Enzyme Inhibitors
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Marine Toxins
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Oxazoles
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bcl-X Protein
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Okadaic Acid
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calyculin A
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Cycloheximide
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Protein Phosphatase 1
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Protein Phosphatase 2
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Emetine