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PTEN LOSS ANTAGONIZES AGING THROUGH PROMOTING
REGENERATION AND PREVENTS OXIDATIVE STRESS INDUCED
CELL DEATH
By
Ni Zeng
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 PHARMACOLOGY AND TOXICOLOGY)
December 2012
Copyright 2012 Ni Zeng
Object Description
| Title | PTEN loss antagonizes aging through promoting regeneration and prevents oxidative stress induced cell death |
| Author | Zeng, Ni |
| Author email | zengni02@gmail.com;nzeng@usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Molecular Pharmacology and Toxicology |
| School | School of Pharmacy |
| Date defended/completed | 2012-05-01 |
| Date submitted | 2012-11-22 |
| Date approved | 2012-11-23 |
| Restricted until | 2012-11-23 |
| Date published | 2012-11-23 |
| Advisor (committee chair) | Stiles, Bangyan |
| Advisor (committee member) |
Johnson, Deborah Okamoto, Curtis |
| Abstract | PTEN is a dual lipid and protein phosphatase that antagonizes the PI3K/AKT signaling cascade and controls multi cellular activities including proliferation, survival and metabolism. Here, I studied its role in aging regulation through investigating how it controls two aging-related processes: tissue regeneration and oxidative stress in two types of cells: pancreatic beta cells and liver hepatocytes. Beta cells undergo a significant aging process with declined proliferation and restricted regeneration as the major phenotypes. I hypothesized that this aging process is controlled by IGF-1, the level of which also declines dramatically with advanced aging. To test that, I selectively deleted Pten in beta cells to activate the IGF-1 signaling. Indeed, Pten deletion not only significantly increases islet proliferation, but also restores the regenerative potential of aged beta cells, confirming the critical role of PTEN in controlling aging. I further demonstrated that such pro-proliferation and anti-aging effects of PTEN are mediated through the cyclinD1/E2F/ Ezh2/p16Ink4a signaling axis. ❧ In addition, I also studied how PTEN regulates oxidative stress response using the liver deletion mouse model. PTEN loss in liver leads to fatty liver early and liver cancer later in life. I found that Pten null hepatocytes are resistant to oxidative stress induced by fatty liver development. Analysis of the molecular mechanism suggested that phosphorylation of the stress responder eIF2α and downregulation of the eIF2α phosphatase CReP are the downstream events of Pten deletion that contribute to the stress resistance. ❧ Together, I showed that PTEN is an important regulator of both regeneration and oxidative stress response during the aging process. Studies of the molecular mechanisms and downstream pathways of PTEN in different tissue context might provide critical insights into how to balance regeneration and oxidative stress to achieve better life quality in the aged individuals. |
| Keyword | aging; AKT; beta cell; IGF-1; PTEN; regeneration |
| 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-m |
| Rights | Zeng, Ni |
| Access conditions | The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the author, as the original true and official version of the work, but does not grant the reader permission to use the work if the desired use is covered by copyright. It is the author, as rights holder, who must provide use permission if such use is covered by copyright. The original signature page accompanying the original submission of the work to the USC Libraries is retained by the USC Libraries and a copy of it may be obtained by authorized requesters contacting the repository e-mail address given. |
| Repository name | University of Southern California Digital Library |
| Repository address | USC Digital Library, University of Southern California, University Park Campus MC 7002, 106 University Village, Los Angeles, California 90089-7002, USA |
| Repository email | cisadmin@usc.edu |
| Archival file | uscthesesreloadpub_Volume6/etd-ZengNi-1339.pdf |
Description
| Title | Page 1 |
| Full text | PTEN LOSS ANTAGONIZES AGING THROUGH PROMOTING REGENERATION AND PREVENTS OXIDATIVE STRESS INDUCED CELL DEATH By Ni Zeng 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 PHARMACOLOGY AND TOXICOLOGY) December 2012 Copyright 2012 Ni Zeng |
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