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TGF‐beta Regulates Alternative Splicing of CD44 by Inducing Smad3 Binding to CD44 pre‐mRNA
Author(s) -
Zhang Ying,
Tripathi Veenu,
Sixt Katherine,
Heller Mary
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.562.15
Subject(s) - alternative splicing , cd44 , rna splicing , exon , gene isoform , smad , transforming growth factor beta , cancer research , biology , tumor progression , messenger rna , microbiology and biotechnology , splicing factor , tgf beta signaling pathway , signal transduction , transforming growth factor , gene , cell , rna , genetics
During late stage of breast cancer, TGF‐beta signaling promotes tumor progression by stimulating EMT, cell invasion and disseminations to distant sites. Previous studies have showed that TGF‐beta supports tumor progression through Smad‐dependent transcription regulation and Smad‐independent translational regulation. A few reports also suggested a role of alternative splicing, which represents another important mechanism of gene regulation, in aggressive cellular behavior induced by TGF‐beta during cancer progression. However, it is still unknown how TGF‐beta regulates alternative splicing. We found that TGF‐beta regulate alternative splicing of CD44 by inducing binding of Smad3 on CD44 pre‐mRNA surrounding regions encoding variant exons to inhibit recruitment of the splicing machinery to variant exons with suboptimal splice sites, thereby promotes a switch in CD44 expression from epithelial variant isoforms to the standard isoform. This isoform switch is essential for breast cancer progression. We show that the interaction of Smad3 with CD44 pre‐mRNA requires both input from TGF‐beta signaling and activation of oncogenic signaling, which occurs selectively in the tumor cells. Thus, Smad3 enables the tumor promoting function of TGF‐beta by serving as a regulator in alternative splicing under oncogenic stimulation in tumor cells.