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IDENTIFICATION OF TWO NEGATIVE REGULATORS OF p53:
H1.2 COMPLEX AND VprBP
by
Kyunghwan Kim
--------------------------------------------------------------------------------------------
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
(BIOCHEMISTY AND MOLECULAR BIOLOGY)
May 2010
Copyright 2010 Kyunghwan Kim
Object Description
| Title | Identification of two negative regulators of p53: H1.2 complex and VprBP |
| Author | Kim, Kyunghwan |
| Author email | Kyunghki@usc.edu; keny0917@hanmail.net |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Biochemistry & Molecular Biology |
| School | Keck School of Medicine |
| Date defended/completed | 2010-03-24 |
| Date submitted | 2010 |
| Restricted until | Unrestricted |
| Date published | 2010-04-28 |
| Advisor (committee chair) | An, Woojin |
| Advisor (committee member) |
Stallcup, Michael Wang, Clay |
| Abstract | p53 is a transcription factor which regulates the cell cycle, DNA repair and apoptosis in response to DNA damage. Even though the mechanisms of p53 accumulation and activation have been extensively studied, little is known about how p53 function is negatively regulated. Here we described H1.2 complex and VprBP as novel negative regulators of p53-mediated transcription.; Linker histone H1 has been generally viewed as a global repressor of transcription by preventing the access of transcription factors to sites in chromatin. However, recent studies suggest that H1 can interact with other regulatory factors for its action as a negative modulator of specific genes. To investigate these aspects, we established a human cell line expressing H1.2, one of the H1 subtypes, for the purification of H1-interacting proteins. Our results showed that H1.2 can stably associate with sets of cofactors and ribosomal proteins which can significantly repress p53-dependent, p300-mediated chromatin transcription. This repressive action of H1.2 complex involves direct interaction of H1.2 with p53, which in turn blocks p300-mediated acetylation of chromatin. YB1 and PURα, two factors present in the H1.2 complex, together with H1.2 can closely recapitulate the repressive action of the entire H1.2 complex in transcription. ChIP and RNAi analyses further confirmed that the recruitment of YB1, PURα and H1.2 to the p53 target gene Bax is required for repression of p53-induced transcription. Therefore, these results reveal a previously unrecognized function of H1 as a transcriptional repressor, as well as the underlying mechanism involving specific sets of factors in this repression process.; HIV-1 Vpr binding protein (VprBP) has been implicated in DNA replication and cell cycle regulation, but its precise role remains unclear. Here we report that VprBP epigenetically regulates p53-induced transcription and apoptotic pathway. VprBP is recruited by p53 to occupy p53-responsive promoters and suppress p53 transactivation in the absence of stress stimuli. To maintain target promoters in an inactive state, VprBP stably binds to nucleosomes by recognizing unacetylated histone H3 tails after the initial recruitment. Promoter-localized deacetylation of H3 tails by HDAC1 is prerequisite for VprBP to tether and act as a bona fide inhibitor at p53 target genes. Consistent with these results, VprBP knockdown leads to activation of p53 target genes that initiate cell cycle arrest and apoptosis upon DNA damage, and causes an increase in DNA damage-induced cell death. Significantly, VprBP is overexpressed in human cancer cells, and this increased level of VprBP is tightly correlated with reduced apoptosis. Our results thus reveal a new role for VprBP in regulation of p53 signaling pathway, as well as molecular mechanisms of cancer development related to VprBP overexpression. |
| Keyword | p53; linker histone; VprBP; chromatin; transcription; histone; acetylation; cancer |
| 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-m2968 |
| Rights | Kim, Kyunghwan |
| 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-Kim-3602 |
| Archival file | uscthesesreloadpub_Volume32/etd-Kim-3602.pdf |
Description
| Title | Page 1 |
| Full text | IDENTIFICATION OF TWO NEGATIVE REGULATORS OF p53: H1.2 COMPLEX AND VprBP by Kyunghwan Kim -------------------------------------------------------------------------------------------- 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 (BIOCHEMISTY AND MOLECULAR BIOLOGY) May 2010 Copyright 2010 Kyunghwan Kim |
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