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A REGULATORY TRANSCRIPTION MODULE OF ZBRK1/KAP1 COMPLEX AND ITS SIGNALING NETWORK IN REGULATING DNA DAMAGE-RESPONSIVE GENES EXPRESSION
by
Yung-Kang Lee
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
(MOLECULAR PHARMACOLOGY AND TOXICOLOGY)
December 2006
Copyright 2006 Yung-Kang Lee
Object Description
| Title | A regulatory transcription module of ZBRK1/KAP1 complex and its signaling network in regulating DNA damage-responsive genes expression |
| Author | Lee, Yung-Kang |
| Author email | yungkanl@usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Molecular Pharmacology & Toxicology |
| School | School of Pharmacy |
| Date defended/completed | 2006-09-21 |
| Date submitted | 2006 |
| Restricted until | Unrestricted |
| Date published | 2006-10-12 |
| Advisor (committee chair) | Ann, David K. |
| Advisor (committee member) |
Duncan, Roger F. Li, Wei |
| Abstract | In pursuit of new SUMOylation targets that regulate the activities of cell cycle progression and mediate cellular apoptosis, a proteomic screening that combined affinity chromatography and tandem mass spectrometry was launched to identify novel targets from SUMO-1 stably-expressed HEK293 cells. With a series of discreet screens and analyses, this effort yields twenty-three SUMOylation candidates, which are found to carry out distinct cellular functions. KAP1 was verified as a bona fide SUMO-1 substrate and a following literature research pointed KAP1 to a novel role in regulating the transcription of a cluster of cell cycle regulator genes and pro-apoptotic genes via its interaction with a transcriptional factor ZBRK1 that bound a 15-bp DNA sequence motif.; Subsequently, the lysines 554, 779 and 804 in KAP1 were identified as the major SUMOylation sites. Using two KAP1 mutants--one deficient in SUMOylation and the other mimics constitutive SUMOylation, the Dox-mediated induction of cell cycle regulator p21WAF1/CIP1 transcription is differentially regulated by KAP1 SUMOylation status. The SUMOylation-dependent modulation in the p21 transcription was achieved through changes in the lysine acetylation and methylation of histone 3 at the p21 promoter. Furthermore, the KAP1 SUMOylation level was transiently decreased upon Dox-exposure, and the introduction of constitutively SUMOylated KAP1 desensitized breast cancer MCF-7 cells to Dox-elicited cell death. Taken together, I provide a novel mechanistic basis underlying the Dox-induced de-repression of p21 transcription, and my results suggest that Dox-induced decrease in KAP1 SUMOylation is essential for Dox-induced p21 expression and subsequent cell growth inhibition in MCF-7 cells.; Further tracking the upstream signaling cascade that leads to the presumed Dox-induced KAP1 de-SUMOylation, my preliminary results indicated that SUMO-specific protease SENP1 and DNA damage-responsive protein kinase ATM might have served for this purpose. Lastly, a proposed future studies and the rationale underlying it was described herein. |
| Keyword | KAP1 SUMOylation; histone acetylation methylation; DNA double strand break damage; Doxorubicin; ATM ATR; SUMO-specific protease SENP |
| 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-m91 |
| Contributing entity | University of Southern California |
| Rights | Lee, Yung-Kang |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | cisadmin@dots.usc.edu |
| Filename | etd-Lee-20061012 |
| Archival file | uscthesesreloadpub_Volume26/etd-Lee-20061012.pdf |
Description
| Title | Page 1 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@dots.usc.edu |
| Full text | A REGULATORY TRANSCRIPTION MODULE OF ZBRK1/KAP1 COMPLEX AND ITS SIGNALING NETWORK IN REGULATING DNA DAMAGE-RESPONSIVE GENES EXPRESSION by Yung-Kang Lee 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 (MOLECULAR PHARMACOLOGY AND TOXICOLOGY) December 2006 Copyright 2006 Yung-Kang Lee |
