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MOLECULAR ANALYSIS OF HIGH MOBILITY GROUP A2 (HMGA2)
ONCOGENIC FUNCTION
by
Angela Ying-Jian Li
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(PHARMACEUTICAL SCIENCES)
August 2008
Copyright 2008 Angela Ying-Jian Li
Object Description
| Title | Molecular analysis of high mobility group A2 (HMGA2) oncogenic function |
| Author | Li, Angela Ying-Jian |
| Author email | angelali@usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Pharmaceutical Sciences |
| School | School of Pharmacy |
| Date defended/completed | 2008-05-19 |
| Date submitted | 2008 |
| Restricted until | Unrestricted |
| Date published | 2008-07-18 |
| Advisor (committee chair) | Wang, Clay C. |
| Advisor (committee member) |
Ann, David K. Hacia, Joseph Haworth, Ian Shen, Wei-Chiang |
| Abstract | HMGA2 is located on chromosome 12q13-15, which is frequently amplified or subjected to chromosomal rearrangements in human cancers. However, the multitudinous tumorigenic roles of HMGA2 remain elusive. In our first study, we provide molecular and cellular evidence that HMGA2 forms complexes with Ku70/80-DNA, hence conferring deficiency in overall and precise NHEJ-mediated DNA repair. This is reflected by a prolonged duration of DNA-PKcs phosphorylation at Ser-2956 and Thr-2609 in response to DNA damage. Consequently, HMGA2 alone is sufficient to induce spontaneous chromosome aberrations in WI-38 cells. Using real-time imaging in living cells, a sustained accumulation of DNA-PKcs at DSB sites in HMGA2-expressing cells receiving microirradiation was observed, resembling to observations found among DNA-PKcs mutants. Furthermore, knocking down HMGA2 or abolishing HMGA2-DNA interaction reverses HMGA2-elicited dysregulation of DNA-PKcs activation profile and the enhanced susceptibility to DSBs. Lastly, HMGA2 expression correlates with unfavorable treatment outcome in breast cancer. Together, these results support a model in which the interplay between Ku70/80 and HMGA2 interferes with NHEJ and shed light on a novel role of HMGA2 in promoting genome instability.; Human telomerase activity is tightly regulated by the expression of hTERT and reactivation of telomerase is required for most neoplasia. In our second study, Affymetrix microarray gene expression analyses indicate an inverse co-regulation of hTERT and HDAC4 by HMGA2 in HeLa cells. Functionally, HMGA2 conveys significantly lower HDAC activities, enhanced basal telomerase activities, and resistance to two different classes of telomerase inhibitors. Co-transfection of HMGA2 or treatment with SAHA, an HDAC inhibitor, renders hTERT-reporter activation in a dose-dependent manner. Furthermore, HMGA2 expression results in increased localized H3-K9acetylation in hTERT proximal promoter via HDAC4 downregulation and/or proteinprotein interaction of HMGA2 with Sp1 or HDAC4. Observations on the reactivation of telomerase activity in WI-38 cells transduced with lenti-HMGA2 and a positive correlation between the expression levels of HMGA2 and hTERT (p=0.01) from 34 breast cancer patient samples further confirm a critical role for HMGA2 to induce hTERT expression. Together, we propose that a combination of downregulating HDAC4 expression, hence activity and decreased recruitment of HDAC4 through Sp1 to hTERT promoter, are exploited by HMGA2 during oncogenesis. |
| Keyword | HMGA2; NHEJ; DNA-PK; DSBs; hTERT; telomere |
| 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 |
| Type | texts |
| Legacy record ID | usctheses-m1356 |
| Rights | Li, Angela Ying-Jian |
| 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-Li-20080718 |
| Archival file | uscthesesreloadpub_Volume14/etd-Li-20080718.pdf |
Description
| Title | Page 1 |
| Full text | MOLECULAR ANALYSIS OF HIGH MOBILITY GROUP A2 (HMGA2) ONCOGENIC FUNCTION by Angela Ying-Jian Li A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (PHARMACEUTICAL SCIENCES) August 2008 Copyright 2008 Angela Ying-Jian Li |
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