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Nat Commun ; 12(1): 4624, 2021 07 30.
Article in English | MEDLINE | ID: mdl-34330897

ABSTRACT

AKT-phosphorylated IWS1 regulates alternative RNA splicing via a pathway that is active in lung cancer. RNA-seq studies in lung adenocarcinoma cells lacking phosphorylated IWS1, identified a exon 2-deficient U2AF2 splice variant. Here, we show that exon 2 inclusion in the U2AF2 mRNA is a cell cycle-dependent process that is regulated by LEDGF/SRSF1 splicing complexes, whose assembly is controlled by the IWS1 phosphorylation-dependent deposition of histone H3K36me3 marks in the body of target genes. The exon 2-deficient U2AF2 mRNA encodes a Serine-Arginine-Rich (RS) domain-deficient U2AF65, which is defective in CDCA5 pre-mRNA processing. This results in downregulation of the CDCA5-encoded protein Sororin, a phosphorylation target and regulator of ERK, G2/M arrest and impaired cell proliferation and tumor growth. Analysis of human lung adenocarcinomas, confirmed activation of the pathway in EGFR-mutant tumors and showed that pathway activity correlates with tumor stage, histologic grade, metastasis, relapse after treatment, and poor prognosis.


Subject(s)
Adenocarcinoma of Lung/genetics , Cell Cycle/genetics , Cell Proliferation/genetics , ErbB Receptors/genetics , Lung Neoplasms/genetics , Proto-Oncogene Proteins c-akt/genetics , RNA-Binding Proteins/genetics , Splicing Factor U2AF/genetics , Transcription Factors/genetics , A549 Cells , Adenocarcinoma of Lung/metabolism , Animals , Cell Line, Tumor , ErbB Receptors/metabolism , Gene Expression Profiling/methods , Gene Expression Regulation, Neoplastic , HEK293 Cells , Humans , Kaplan-Meier Estimate , Lung Neoplasms/metabolism , Mice, Inbred NOD , Mice, Knockout , Mice, SCID , Mutation , Phosphorylation , Proto-Oncogene Proteins c-akt/metabolism , RNA Splicing , RNA-Binding Proteins/metabolism , Splicing Factor U2AF/metabolism , Transcription Factors/metabolism
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