Date of Award

12-2010

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Comparative and Experimental Medicine

Major Professor

Seung Joon Baek

Committee Members

Xuemin Xu, Jay Wimalasena, Sundar Venkatachalam

Abstract

Most human genes undergo alternative splicing, and many abnormal splicing processes are associated with human diseases. However, the molecular relationship between alternative splicing and tumorigenesis is not well understood. Here, we identified novel Krüppel-like factor 4 (KLF4) splicing variants produced by exon skipping in human cancer cell lines as well as colon tumor tissues. To elucidate the mechanism involved in KLF4 alternative splicing, we developed KLF4 minigene system and found that RNA binding motif protein 5 (RBM5) plays an important role in KLF4 splicing, as assessed by gain and loss of functional studies. Several anti-tumorigenic compounds were also tested for KLF4 splicing. Interestingly, sulindac sulfide restored wild type KLF4 (KLF4L) expression and this is mediated by dephosphorylation of RBM5. Another splicing variant, small KLF4 (KLF4S), localizes in the cytoplasm and nucleus, and antagonizes transcriptional activity of wild type KLF4. Our data suggest that RBM5 plays a pivotal role in the alternative splicing of KLF4, and these splicing variant forms may impact tumorigenesis.

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