Date of Award

2012

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biochemistry and Molecular Biology

College

College of Graduate Studies

First Advisor

Yusuf A. Hannun

Second Advisor

Steven A. Rosenzweig

Third Advisor

Garry Gilkeson

Fourth Advisor

Ashley Cowart

Fifth Advisor

Narendra Banik

Sixth Advisor

John E. Baatz

Abstract

Since their discovery over a century ago, sphingolipids have riddled and fascinated the scientific community with benchmarks of progress including the identification of the enzymatic defects in the lysosomal storage diseases and the discovery of their involvement in cellular processes. Excluding sphingosine-1-phosphate with its associated G-protein coupled receptors, a staggering gap still persists in our understanding of the mechanisms related to the functions of the sphingolipids, ceramide and sphingosine. Moreover, in spite of the impressive amount of literature implicating ceramide in biological processes, precise and well-documented roles in biology for specific ceramide-producing enzymes are surprisingly rare. To further investigate the biological role of ceramide, we made the general hypothesis that ceramide produced from specific enzymes in the salvage pathway of sphingolipid metabolism plays a role in regulating stress signaling. In this work, we first aimed to identify novel protein targets of ceramide in the context of serine/threonine phosphatases to address possible mechanisms of ceramide action in stress signaling, and second to define specific roles for salvage pathway enzymes in the regulation of IL-6, a proinvasive cytokine. As a result of this work we identified a novel class of serine/threonine phosphatases, PP2C/PPM, to be activated by ceramide. This opens a new avenue of research to investigate ceramide-mediated mechanisms in biology. Additionally, this work demonstrates, essentially for the first time, involvement of the ASM/ceramide pathway in the activation of p38 signaling, resulting in the induction of IL-6. Our findings fit with previous work connecting PKC activation to ASM, while casting ASM in a new light as a potential proinvasive factor in cancer.

Rights

All rights reserved. Copyright is held by the author.

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