Skip to Main Content
 

Global Search Box

 
 
 
 

Files

File List


ucin1014751166.pdf (3.16 MB)

ETD Abstract Container

Abstract Header

HBx-MEDIATED DISRUPTION OF p53 TUMOR SUPPRESSOR PROTEIN FUNCTION LEADING TO RE-ACTIVATION OF A SILENCED TUMOR MARKER GENE

OGDEN, STACEY KATHRYN
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1014751166

Abstract Details

2002, PhD, University of Cincinnati, Medicine : Molecular Genetics, Biochemistry and Microbiology.
Chronic infection with Hepatitis B Virus (HBV) is a predominant risk factor associated with development of hepatocellular carcinoma (HCC). Individuals who are chronically infected with HBV are over 200-times more likely to develop HCC than those who are not infected. Multiple studies have implicated the virally encoded X protein (HBx) as the candidate oncoprotein responsible for cellular transformation. HBx forms a complex with cellular p53 tumor suppressor protein to result in modification of p53-mediated gene regulation, DNA damage detection and modulation of apoptosis. The developmentally silenced a-fetoprotein (AFP) tumor marker gene, which is transcriptionally repressed by p53, is tightly correlated with HCC development: it is reactivated in over 80% of all liver carcinomas. p53 mediates transcriptional repression of AFP through an over-lapping HNF-3/Smad4/p53 binding element located within the developmental repressor domain of the AFP promoter. Here, using AFP as a model gene, we have examined the mechanism by which p53 facilitates transcriptional repression, and how this repression is disrupted upon p53-HBx interaction. In vitro chromatin assembled transcription analysis and enzyme accessibility studies demonstrate that p53 association at the overlapping binding element is required during chromatin assembly for reorganization of AFP promoter chromatin structure to result in occlusion of restriction enzymes and general transcription factors from the transcription start site. Protein-DNA binding assays show that p53 association at this element is required to recruit mSin3A co-repressor and stabilize association of a putative Smad4 and SnoN containing co-repressor complex with AFP chromatin templates. HBx-mediated reactivation of AFP is achieved through direct p53-HBx interaction resulting in disruption of SnoN co-repressor binding to AFP chromatin templates.
Dr. Michelle Craig Barton (Advisor)
136 p.
gene regulation; liver cancer; chromatin structure modification; In vitro transcription

Recommended Citations

Citations

  • OGDEN, S. K. (2002). HBx-MEDIATED DISRUPTION OF p53 TUMOR SUPPRESSOR PROTEIN FUNCTION LEADING TO RE-ACTIVATION OF A SILENCED TUMOR MARKER GENE [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1014751166

    APA Style (7th edition)

  • OGDEN, STACEY. HBx-MEDIATED DISRUPTION OF p53 TUMOR SUPPRESSOR PROTEIN FUNCTION LEADING TO RE-ACTIVATION OF A SILENCED TUMOR MARKER GENE. 2002. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1014751166.

    MLA Style (8th edition)

  • OGDEN, STACEY. "HBx-MEDIATED DISRUPTION OF p53 TUMOR SUPPRESSOR PROTEIN FUNCTION LEADING TO RE-ACTIVATION OF A SILENCED TUMOR MARKER GENE." Doctoral dissertation, University of Cincinnati, 2002. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1014751166

    Chicago Manual of Style (17th edition)

ucin1014751166
859
© 2002, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.