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Dissertation
Hepatitis B virus X protein localizes to mitochondria and regulates apoptosis in primary rat hepatocytes
Doctor of Philosophy (Ph.D.), Drexel University
12 Jan 2009
DOI:
https://doi.org/10.17918/00000627
Abstract
Approximately 350 million individuals are chronically infected with the hepatitis B virus (HBV). Chronic HBV infections are associated with the development of hepatocellular carcinoma (HCC). HBV encodes seven viral proteins, including the nonstructural X protein (HBx). The results of studies from numerous groups suggest that the development of HBV-associated HCC involves both the consequences of immune-mediated destruction of HBV-infected hepatocytes and activities of HBV proteins such as HBx. HBx is a multi-functional protein involved in the regulation of HBV replication, cellular transcription and signal transduction pathways, cell cycle progression and apoptosis; however, which HBx activities contribute to the development of HBV-associated HCC is undefined. Many of the previously reported studies that analyzed HBx localization and regulation of apoptotic pathways were conducted in immortalized or transformed cells, and the alterations that have transformed or immortalized these cells may impact HBx localization and regulation of apoptotic pathways. We used cultured primary rat hepatocytes as a biologically relevant model system to characterize the mitochondrial localization of HBx and the effect of HBx expression on apoptosis. Importantly, we analyzed the effect of HBx on apoptosis when expressed in the absence of other HBV proteins and in the context of HBV replication. XIV We demonstrate that a fraction of HBx localizes to the outer mitochondrial membrane. We also show that HBx activation of nuclear factor kappa B (NF-[kappa]B) prevents apoptosis in cultured primary rat hepatocytes. However, when activation of NF-[kappa]B is blocked, HBx induces apoptosis through modulation of the mitochondrial permeability transition pore (MPTP). These results suggest that the effect of HBx on apoptosis can vary, depending on the status of NF-[kappa]B. Collectively, these results define potential pathways through which HBx may act in order to modulate mitochondrial physiology and apoptosis, and may provide a mechanistic link between HBx expression and the development of HBV-associated HCC.
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Details
- Title
- Hepatitis B virus X protein localizes to mitochondria and regulates apoptosis in primary rat hepatocytes
- Creators
- Amy J. Clippinger
- Contributors
- Michael Bouchard (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xiv, 242 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; College of Medicine; Drexel University
- Other Identifier
- 991014970216004721