Date of Award

2016

Document Type

Open Access Thesis

Department

Chemistry and Biochemistry

Sub-Department

College of Arts and Sciences

First Advisor

Mythreye Karthikeyan

Abstract

Bone morphogenetic protein 2/4 (BMP2/4), members of the transforming growth factor β (Tgf-β) superfamily, play a dichotomous role in the progression of cancers through cell growth suppression and the enhancement of tumorigenesis in a variety of cancers. Cyclin dependent kinase 8 (CDK8), a protein kinase that regulates gene transcription, is involved in a variety of cancers including breast and pancreatic cancers as well as in mediating BMP2 signaling via its canonical Smad1 pathway. Our studies show that BMP4 induced EMT signals primarily though Smad1 and that Yap1, a transcriptional co-activator, is necessary for BMP4 induced EMT. Using a highly specific ATP competitive inhibitor of Cdk8 and its twin kinase Cdk19, Senexin B, we find that blocking the kinase activity of Cdk8/19 decreases BMP4 transcription of genes associated with EMT and inhibits BMP4 induced invasion. By separately reducing the expression of Cdk8 and Cdk19, we show for the first time that these kinases have both distinct and overlapping functions. Our findings suggest that Cdk8 and Cdk19, along with Yap1, are crucial for dictating BMP4/Smad1 responses during EMT and each of these factors could serve as a selective therapeutic target to block BMP4 signaling in cancer progression.

Rights

© 2016, Anne Elizabeth Serrao

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