Characterization of the role of acid ceramidase in adrenocortical steroid hormone biosynthesis

Show full item record

Please use this identifier to cite or link to this item:

Title: Characterization of the role of acid ceramidase in adrenocortical steroid hormone biosynthesis
Author: Lucki, Natasha Chrystman
Abstract: Sphingolipids modulate multiple cellular functions, including steroid hormone biosynthesis. Sphingosine is an antagonist ligand for the nuclear receptor steroidogenic factor 1 (SF-1), which is the primary transcriptional regulator of most steroidogenic genes. Furthermore, sphingosine-dependent repression of SF-1 function is dependent on the expression of acid ceramidase (ASAH1), an enzyme that forms sphingosine. Based on these data, I hypothesized that ACTH/cAMP signaling regulates ASAH1 function at both transcriptional and post-transcriptional levels. In addition, because SF-1 is predominantly a nuclear protein, I postulated that ASAH1 modulates SF-1 function and, therefore, steroidogenic gene expression by controlling the nuclear concentrations of SPH. To test these hypotheses, I first examined the effect of chronic ACTH/cAMP signaling on the transcription of the ASAH1 gene. Next, the functional significance of ASAH1 expression in adrenocortical cells was probed by generating an ASAH1-knockdown cell line. I subsequently characterized the role of ASAH1 as a transcriptional nuclear receptor coregulator. Finally, I defined the role of sphingosine-1-phosphate, a bi-product of ASAH1 activity, in the acute phase of cortisol biosynthesis. Using a variety of experimental approaches, I identified cAMP response element binding protein as an essential transcriptional activator of the ASAH1 gene. Analysis of adrenocortical cells lacking ASAH1 revealed that ASAH1 is a global regulator of steroidogenic capacity. Furthermore, I identified ASAH1 as a nuclear protein and defined the molecular determinants of the interaction between ASAH1 and SF-1. Collectively, this body of work establishes the integral role of ASAH1 in the regulation of ACTH-dependent adrenocortical cortisol biosynthesis.
Type: Dissertation
Date: 2011-11-14
Publisher: Georgia Institute of Technology
Subject: Steroidogenic factor 1
Acid ceramidase
Adrenal gland
Adrenal cortex
Adrenocortical hormones
Steroid hormones
Department: Biology
Advisor: Committee Chair: Sewer, Marion; Committee Co-Chair: Merrill, Al; Committee Member: Boyan, Barbara; Committee Member: Fan, Yuhong; Committee Member: McCarty, Nael
Degree: PhD

All materials in SMARTech are protected under U.S. Copyright Law and all rights are reserved, unless otherwise specifically indicated on or in the materials.

Files in this item

Files Size Format View
lucki_natasha_c_201112_phd.pdf 20.97Mb PDF View/ Open

This item appears in the following Collection(s)

Show full item record