We investigate three areas (see below) of gene regulation involved in carcinogenesis, including tumor virus-host cell interactions and cell stress: 1) the role of the hepatitis B virus X protein (HBx) in viral infection, carcinogenesis and pathogenesis; 2) the mechanism for inhibition of cellular protein synthesis by oncogenic viruses such as adenovirus, and the control of protein synthesis during carcinogenesis, cell stress and hypoxia; and 3) the mechanism and regulation of selective degradation of short-lived proto-oncogene and cytokine mRNAs. Applications of this work forms the basis of our additional research efforts in gene therapy and development of novel adenovirus vectors.

Hepatitis B virus (HBV) is a para-retrovirus that infects the liver and is strongly associated with human liver cancer, a major form of cancer worldwide. The HBx protein is a regulatory protein that is involved in HBV infection and carcinogenesis. We previously established that HBx activates Src-Ras signal transduction pathways, which are critical for activation of many transcription factors by HBx, and for HBx activation of HBV reverse-transcription and DNA replication. We have also shown that HBx causes a loss of early cell-cycle checkpoint controls, it is likely involved in HBV pathogenesis by cytokines, and it may play a role in liver cancer caused by Hepatitis B virus infection. Ongoing studies are directed toward understanding the mechanism by which HBx activates Src tyrosine kinase signalling, how this leads to activation of HBV replication, and the role of HBx in viral pathogenesis and cellular transformation.


The control of mRNA translation is a highly regulated process. Translational control is an important target for upregulation as a component of malignant transformation of cells during carcinogenesis by oncogenic viruses and by other means. Our research in this area is directed toward understanding how cellular protein synthesis is controlled by oncogenic viruses such as adenovirus, by the lack of oxygen (hypoxia) which often limits tumor growth, and how it is upregulated as a component of tumor invasiveness and malignancy. We have established that adenovirus remodels the cap-initiation complex required for translation of mRNAs by utilizing a viral protein that displaces a protein kinase from the complex, making it specific for viral mRNAs. We have also shown that heat shock induced cell stress inhibits cellular protein synthesis by mediating dissociation of the cap-initiation complex using heat shock proteins. Other studies have shown that adenovirus and heat shock mRNAs utilize the altered cap-initiation complex to undergo an unusual form of translation initiation known as ribosome shunting. Ongoing studies are directed to understanding the mechanism of ribosome shunting, the altered function of adenovirus remodeled cap-initiation complexes, and the pathways which control protein synthesis during carcinogenesis and hypoxia.

Many of the most powerful biological regulators of cell growth and proliferation are encoded by unstable mRNAs which are targeted for rapid degradation by the cell. The loss of rapid degradation of these mRNAs can result in oncogenic transformation of the cell. Targeted degradation of short-lived cytokine and proto-oncogene mRNAs is controlled in a regulated manner by an AU-rich element (ARE) located in the 3' noncoding region, and by several proteins that bind this sequence. We have shown that activation of the ARE for mRNA decay involves cotranslation of the mRNA by ribosomes, and involves the ubiquitin-proteasome pathway. We are studying the mechanism for cotranslational degradation of short-lived mRNAs, the involvement of the ubiquitin-proteasome pathway in regulation of cytokine and proto-oncogene mRNA stability, and the complex of proteins that act on the AU-rich element to control degradation.