Date of Award

Spring 1-1-2017

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

First Advisor

Leslie A. Leinwand

Second Advisor

Tin Tin Su

Third Advisor

Dylan Taatjes

Fourth Advisor

Robin Dowell

Fifth Advisor

Andreas Hoenger

Abstract

Cancer is a disease of dysregulated gene expression in which many developmental programs are hijacked. One such program is the cellular response to hypoxia, or low oxygen stress. Hypoxia-inducible factors (HIF) govern the cell’s response to this stressor. While much is known about the transcriptional programs HIF directs, comparably little is known about the transcriptional regulation enabling the progression of this response. In the first two chapters of this thesis, I report on the current state of knowledge of the HIF transcriptional program and present new evidence for the role of the conserved coactivator, TIP60, on HIF1A, the primary driver of the cellular response to hypoxia and potent oncogene.

Sarcomeric myosin heavy chain proteins are mechanochemical enzymes that provide the mechanical force required for muscle contraction. These proteins belong to a long-studied and well-described family with numerous implications in heart and skeletal muscle diseases. In the final chapter of my thesis, I present evidence for the exclusion of a myosin heavy chain protein, MYH7B, from mammalian cardiac tissue as a beneficial evolutionary adaptation despite its abundant expression in mammal’s evolutionary neighbor, reptiles.

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