Date of Graduation

2016

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Biochemistry

Committee Chair

Steven M Frisch

Committee Co-Chair

Karen Martin

Committee Member

Peter Mathers

Committee Member

David M Smith

Committee Member

Peter Stoilov

Abstract

Tumor progression and developmental morphogenesis require transient or stable Epithelial-Mesenchymal transitions (EMT) to modulate epithelial junctional complexes allowing programmed migration, invasion, and anoikis resistance of cells. Grainyhead-like-2 (GRHL2), an epithelial master-regulatory transcription factor, suppresses EMT and causes a mesenchymal-epithelial transition to the default epithelial phenotype. This body of work investigates the role of GRHL2 in kidney cancer, in kidney development using a kidney specific GRHL2 knockout mouse model, and in tubulogenesis using Madin-Darby Canine Kidney (MDCK) cells. In kidney cancer, GRHL2 was not expressed in the normal kidney proximal tubule epithelial cells which are thought to be the progenitors of clear cell renal cell carcinomas. However, GRHL2 could function as biomarker to differentiate renal cell carcinoma subtypes. In kidney development, a large amount of evidence suggests Grhl2 is a critical regulator of this process. However, kidney specific Grhl2 knockout mice did not elucidate the role of Grhl2 in the developing kidney for technical reasons, and this area needs to be further investigated. In the MDCK model, GRHL2 was required for cystogenesis, but it suppressed Hepatocyte Growth Factor-induced tubulogenesis, a process requiring transient, partial EMT. Subsequent results demonstrated that GRHL2 suppressed tubulogenesis by inhibiting the histone acetyltransferase co-activator, p300, thereby preventing the induction of matrix metalloproteases and other p300-dependent genes required for tubulogenesis. A thirteen amino acid region (425-437aa) of GRHL2 was required and sufficient for the inhibition of p300 histone acetyltransferase activity, the suppression of tubulogenesis and the interference with EMT. These results demonstrate that p300 is required for EMT plasticity occurring in tubulogenesis or tumor progression, and that GRHL2 suppresses EMT in both contexts, through inhibition of p300.

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