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Alternative splicing of Kruppel‐like factor 4 plays a pivotal role in human tumorigenesis
Author(s) -
Bahn Jae Hoon,
Lee SeongHo,
Baek Seung Joon
Publication year - 2010
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.24.1_supplement.881.1
Subject(s) - minigene , rna splicing , splicing factor , klf4 , alternative splicing , carcinogenesis , exon , biology , cancer research , intron , exonic splicing enhancer , microbiology and biotechnology , genetics , gene , transcription factor , rna , sox2
Most human genes undergo alternative splicing, and many abnormal splicing processes are associated with disease including cancer. However, the relationship between alternative splicing and tumorigenesis is not well‐understood. Here, we found that novel Kruppel‐like factor 4 (KLF4) splicing variants produced by exon skipping could play a role during tumorigenesis in several human cancer cell lines. The human KLF4 gene produces at least three splicing variants, and one of them, small KLF4 (KLF4S), antagonizes large KLF4 (KLF4L) activity. To further investigate KLF4 splicing mechanism, we developed the KLF4 minigene and mutation of the 3′ splice site in the KLF4 intron 2 plays a pivotal role in the KLF4 splicing ratio. Interestingly, sulindac sulfide treatment restored KLF4L transcript and phosphorylation of the RNA binding motif 5 (RBM5) was decreased in HCT‐116 cells. Furthermore, mutation of the RBM5 phosphorylation site (S69A) decreased the KLF4 splicing event. Over‐expression and RBM5 siRNA also changed the KLF4 splicing ratio. Our data suggest that phosphorylation of RBM5 and the cis‐acting element in the 3′ splice site regulate alternative splicing of KLF4, which is altered during tumorigenesis.