التفاصيل البيبلوغرافية
| العنوان: |
Characterization of the role of acid ceramidase in adrenocortical steroid hormone biosynthesis |
| المؤلفون: |
Lucki, Natasha Chrystman |
| بيانات النشر: |
Georgia Institute of Technology, 2011. |
| سنة النشر: |
2011 |
| المجموعة: |
Georgia Tech Electronic Thesis and Dissertation Archive |
| مصطلحات موضوعية: |
Steroidogenic factor 1, Acid ceramidase, Sphingolipid, Adrenal gland, Cortisol, Sphingosine, Adrenal cortex, Adrenocortical hormones, Steroid hormones, Glycosphingolipids |
| الوصف: |
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. |
| Original Identifier: |
oai:smartech.gatech.edu:1853/42804 |
| نوع الوثيقة: |
Dissertation |
| الإتاحة: |
http://hdl.handle.net/1853/42804Test |
| رقم الانضمام: |
edsndl.GATECH.oai.smartech.gatech.edu.1853.42804 |
| قاعدة البيانات: |
Networked Digital Library of Theses & Dissertations |
