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ROLE OF GH/IGF-1 SIGNALING IN OXIDATIVE STRESS, DNA DAMAGE AND
CANCER
by
Priya Balasubramanian
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(MOLECULAR BIOLOGY)
August 2010
Copyright 2010 Priya Balasubramanian
Object Description
| Title | Role of GH/IGF-1 signaling in oxidative stress, DNA damage and cancer |
| Author | Balasubramanian, Priya |
| Author email | priyabal@usc.edu; bpriyaiyer@gmail.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Molecular Biology |
| School | College of Letters, Arts and Sciences |
| Date defended/completed | 2010-05-11 |
| Date submitted | 2010 |
| Restricted until | Unrestricted |
| Date published | 2010-07-30 |
| Advisor (committee chair) | Longo, Valter D. |
| Advisor (committee member) |
Goodman, Steven Pike, Christian |
| Abstract | Reduced signaling of the Insulin like Growth Factor 1 (IGF-1) pathway in mammals or that of its orthologs in lower organisms is known to increase lifespan and protect against oxidative stress and age-related pathologies. IGF-1 is mainly synthesized in the liver in response to Growth Hormone (GH). Mice with reduced GH signaling, for example the Ames dwarf, Snell dwarf or the Growth Hormone Receptor Knock Out (GHRKO) mice are smaller in size, have longer lifespans, increased insulin sensitivity and are protected against cancer.; In humans, mutations in the Growth Hormone Receptor (GHR) lead to Growth Hormone Receptor Deficiency (GHRD) also known as Laron Syndrome which is characterized by extremely low levels of IGF-1 and dwarfism. Only one case of non-lethal cancer and no cases of diabetes have been observed in a population of about one-hundred GHRD individuals from southern Ecuador in the last twenty two years. This indicates that reduced GH signaling can protect against age-related diseases in humans as well.; Primary, non-cancerous, Human Mammary Epithelial Cells (HMEC) were incubated with serum from GHRD individuals or their unaffected control relatives. GHRD serum protected these cells against oxidative DNA damage and also promoted apoptosis in damaged cells by a mechanism that was reversed by IGF-1. Microarray analysis of genes expression changes between HMEC incubated with GHRD or control serum indicates the upregulation of stress protective genes such as the mitochondrial SOD (SOD2) and downregulation of growth factor signaling pathways such as Ras, PKA and Tor. Yeast lacking TOR1, RAS2, and SCH9 (S6K), 3 orthologs of central IGF-1 signaling genes displayed a major decrease in age-dependent mutations. This indicates that the mechanisms responsible for protection against DNA damage and cancer are highly conserved in lower organisms and humans.; Analysis of Ras signaling in mammalian cells shows that it can downregulate FoxO transcription factor activity. FoxO is already known to be downregulated by IGF-1 signaling via Akt and increased FoxO activity can not only enhance expression of stress protective genes, for example, SOD2, but also participate in regulating apoptosis. Upregulation of FoxO by inhibition of the p38 MAP kinase increases SOD2 protein levels and protects HepG2 cells against oxidative stress. It is possible that p38 is a mediator of Ras signaling to FoxO.; The studies described in this dissertation reveal mechanisms by which a reduction in GH/IGF-1 signaling could protect against DNA damage and cancer in humans. |
| Keyword | growth hormone; growth hormone receptor deficiency; insulin like growth factor-1; cancer; diabetes; Ras; p38; FoxO; oxidative stress |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m3223 |
| Rights | Balasubramanian, Priya |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | http://www.usc.edu/isd/libraries/services/ask_a_librarian/email/ |
| Filename | etd-balasubramanian-3845 |
| Archival file | uscthesesreloadpub_Volume44/etd-balasubramanian-3845.pdf |
Description
| Title | Page 1 |
| Full text | ROLE OF GH/IGF-1 SIGNALING IN OXIDATIVE STRESS, DNA DAMAGE AND CANCER by Priya Balasubramanian A Dissertation Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (MOLECULAR BIOLOGY) August 2010 Copyright 2010 Priya Balasubramanian |
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