Protein degradation is a basic process in the living cell. A large fraction of onco- and tumor suppressor proteins are regulated at the level of their stability. Therefore investigation of the mechanisms of proteasomal protein degradation has attracted much attention. For example the p53 level is controlled by the rate of its proteasomal degradation, a process regulated by the Mdm2-ubiquitin-proteasome degradation pathway.We have found a novel pathway that regulates p53 stability. This pathway is regulated by NAD(P)H: quinone oxidoreductase 1 (NQO1). Pharmacological and genetic inhibition of NQO1 induces p53 proteasomal degradation and inhibits p53-mediated apoptosis. NQO1 regulates degradation of p53 by a mechanism that is independent of both Mdm2 and ubiquitin. This pathway is not exclusive for p53. A limited number of other short-lived proteins such as p73 and ODC are regulated by NQO1. Studies have indicated that this pathway may play a role in oncogenesis. The underlying molecular mechanism of this process of protein destabilization is under study.
We study the molecular basis of cell response to DNA damage, in particular double strand break (DSB). We have characterized a novel signaling-pathway that is initiated by DSB and triggers activation of the non-receptor tyrosine kinase c-Abl. This kinase in turn tyrosine phosphorylates the intimately associated p73, a member of p53 tumor suppressor family. This process often elicits apoptosis unless the damage has been repaired or the DNA fragments have been excluded. Thus, the repair machinery and DNA fragments regulate the apoptosis pathway. The nature and composition of this process is under study.
Viruses in order to propagate have to invade cells and to occupy the relevant cellular machinery. How, a given virus with a very limited number of genes can do so is a very basic question but the answers await understanding of the virus genes from one hand and the cellular machineries from other. Hepatitis B virus (HBV) is a common infectious agent worldwide, hence provides an excellent model. HBV is a liver specific virus.Our study revealed that this tropism is determined at the level of both receptor and post-receptor levels, and identified the molecular basis of these processes. We found that the small pX regulatory protein of HBV manipulates the cellular transcription machinery at all possible levels, namely chromatin, enhancer and the basal promoter binding proteins. Cellular proteins, the targets of pX were identified but the list has not been completed.
Gene therapy has attracted much attention but proved partially successful. Viruses that are used for DNA transduction are unsafe. Our aim is to generate non-infectious virus like particles. The individual components are prepared in heterogonous systems and assembled in tube. These particles are expected to be safe and their production is highly reproducible. These "synthetic virions" may revolutionize the whole field of gene transfer technology.