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17?-estradiol regulates the RNA-binding protein Nova1, which then regulates the alternative splicing of estrogen receptor ? in the aging female rat brain.

ABSTRACT: Alternative RNA splicing results in the translation of diverse protein products arising from a common nucleotide sequence. These alternative protein products are often functional and can have widely divergent actions from the canonical protein. Studies in humans and other vertebrate animals have demonstrated that alternative splicing events increase with advanced age, sometimes resulting in pathological consequences. Menopause represents a critical transition for women, where the beneficial effects of estrogens are no longer evident; therefore, factors underlying increased pathological conditions in women are confounded by the dual factors of aging and declining estrogens. Estrogen receptors (ERs) are subject to alternative splicing, the spliced variants increase following menopause, and they fail to efficiently activate estrogen-dependent signaling pathways. However, the factors that regulate the alternative splicing of ERs remain unknown. We demonstrate novel evidence supporting a potential biological feedback loop where 17?-estradiol regulates the RNA-binding protein Nova1, which, in turn, regulates the alternative splicing of ER?. These data increase our understanding of ER alternative splicing and could have potential implications for women taking hormone replacement therapy after menopause.

SUBMITTER: Shults CL

PROVIDER: S-EPMC5705455 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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17β-estradiol regulates the RNA-binding protein Nova1, which then regulates the alternative splicing of estrogen receptor β in the aging female rat brain.

Shults Cody L CL Dingwall Caitlin B CB Kim Chun K CK Pinceti Elena E Rao Yathindar S YS Pak Toni R TR

Neurobiology of aging 20170914

Alternative RNA splicing results in the translation of diverse protein products arising from a common nucleotide sequence. These alternative protein products are often functional and can have widely divergent actions from the canonical protein. Studies in humans and other vertebrate animals have demonstrated that alternative splicing events increase with advanced age, sometimes resulting in pathological consequences. Menopause represents a critical transition for women, where the beneficial effe ...[more]

PMID: 29031089

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Project description:BackgroundAlternative splicing is critical for generating complex proteomes in response to extracellular signals. Nuclear receptors including estrogen receptor alpha (ER?) and their ligands promote alternative splicing. The endogenous targets of ER?:estradiol (E2)-mediated alternative splicing and the influence of extracellular kinases that phosphorylate ER? on E2-induced splicing are unknown.MethodsMCF-7 and its anti-estrogen derivatives were used for the majority of the assays. CD44 mini gene was used to measure the effect of E2 and AKT on alternative splicing. ExonHit array analysis was performed to identify E2 and AKT-regulated endogenous alternatively spliced apoptosis-related genes. Quantitative reverse transcription polymerase chain reaction was performed to verify alternative splicing. ER? binding to alternatively spliced genes was verified by chromatin immunoprecipitation assay. Bromodeoxyuridine incorporation-ELISA and Annexin V labeling assays were done to measure cell proliferation and apoptosis, respectively.ResultsWe identified the targets of E2-induced alternative splicing and deconstructed some of the mechanisms surrounding E2-induced splicing by combining splice array with ER? cistrome and gene expression array. E2-induced alternatively spliced genes fall into at least two subgroups: coupled to E2-regulated transcription and ER? binding to the gene without an effect on rate of transcription. Further, AKT, which phosphorylates both ER? and splicing factors, influenced ER?:E2 dependent splicing in a gene-specific manner. Genes that are alternatively spliced include FAS/CD95, FGFR2, and AXIN-1. E2 increased the expression of FGFR2 C1 isoform but reduced C3 isoform at mRNA level. E2-induced alternative splicing of FAS and FGFR2 in MCF-7 cells correlated with resistance to FAS activation-induced apoptosis and response to keratinocyte growth factor (KGF), respectively. Resistance of MCF-7 breast cancer cells to the anti-estrogen tamoxifen was associated with ER?-dependent overexpression of FGFR2, whereas resistance to fulvestrant was associated with ER?-dependent isoform switching, which correlated with altered response to KGF.ConclusionE2 may partly alter cellular proteome through alternative splicing uncoupled to its effects on transcription initiation and aberration in E2-induced alternative splicing events may influence response to anti-estrogens.

Dataset Information

17?-estradiol regulates the RNA-binding protein Nova1, which then regulates the alternative splicing of estrogen receptor ? in the aging female rat brain.

Publications

17β-estradiol regulates the RNA-binding protein Nova1, which then regulates the alternative splicing of estrogen receptor β in the aging female rat brain.

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