Research Groups

Mammalian Biology: Virology

Research Interests and Description

Staff Research Scientist: Vijay Kumar

Group Leader: Shahid Jameel

Group Members

Research Interests

Description of Research

Cell cycle deregulation by HBx
The exact role of HBx in deregulation of cell cycle and establishment of a permissive environment for hepatocellular carcinoma (HCC) has remained elusive. Our cell culture-based studies suggested a direct interaction between HBx and cyclin E/A-cdk2 complex. This interaction appeared to deregulate the cell cycle by potentiating cdk2 activity and destabilizing the cdk inhibitor p27Kip1. Interference with signaling cascades known to be activated by HBx suggested a constitutive requirement of Src kinases for the association of HBx with these complexes. HBx mutants that did not interact with cyclin E/A, failed to destabilize p27Kip1 or deregulate cell cycle. Thus, HBx seems to deregulate cell cycle by interacting with the key cell cycle regulators independent of its well established role in transactivation. Currently, we are focusing on the role of HBx in chromatin remodeling to understand the mechanisms underlying the dysregulation of gene expression and DNA replication in hepatocytes.
Oncogenic co-operation between HBx and c-Myc
HBx is known to stimulate a number of signaling cascades such as MAPK, PI3K and Src. Activation of MAPK in turn stimulates a wide range of transcriptional factors like c-jun, c-fos and c-myc that are essential for cellular growth, differentiation and apoptosis. Our experiments with virosome-based hepatic delivery of the HBx gene in mice showed that through expression of HBx was associated with sustained activation of MAP kinases and AP-1 proteins but no cell transformation or tumor development in vivo. Failure of tumor development in these mice suggested that HBx alone may not be tumorigenic and thus, may require other cellular factor(s). Amplification of myc genes and their over-expression is a common observation in virus-infected woodchucks and ground squirrel and has been correlated with development of liver-specific tumors in these mammals. Considering this may well to be one of the mechanisms associated with human HCC development, the mechanism of oncogenic co-operation between HBx and c-Myc was investigated in human hepatoma cells. We observed that c-Myc over-expression was associated with apoptotic death of hepatoma cells which was mediated by c-fos and p38 MAP kinase pathway. However, in the presence of HBx, the apoptotic signals triggered by c-Myc were abrogated leading to increased cell survival. Further, there was also a marked increase in the biochemical stability of c-Myc  in the presence of HBx due to decreased ubiquitination of the former. We showed that HBx interfered with the ubiquitination process through a direct interaction with the ubiquitin ligase Skp2.
Transgenic models of HCC and their application
Using bicistronic recombinants such as X15-myc with the ability to co-express viral HBx and c-myc genes in liver, earlier we reported the development of transgenic mice that would develop liver-specific tumors with histological features similar to human HCC. The control transgenic mice expressing either HBx or c-Myc genes do not develop the above phenotype. These observations suggested an oncogenic co-operativity between the two proteins leading to HCC. The X15-myc oncomouse has been successfully used for screening natural product derived agents with hepatoprotecitive and anticancer activities. We are also looking for new cancer biomarkers and developing novel therapeutic strategies for liver cancer using our oncomouse models.

Recent Publications

Mukherji, A., Janbandhu, V.C., Kumar, V. 2009. HBx protein modulates PI3K/Akt pathway to overcome gentoxic stress-induced destabilization of cyclin D1 and arrest of cell cycle. Indian J. Biochem. Biophys. 46, 37-44

Mukherji, A., Janbandhu, V.C., Kumar, V. 2008. GSK-3beta-dependent destabilization of cyclin D1 mediates replicational stress-induced arrest of cell cycle. FEBS Lett. 582, 1111-1116

Mukherji, A., Janbandhu, V.C., Kumar, V. 2007. HBx-dependent cell cycle deregulation involves interaction with cyclin E/A-cdk2 complex and destabilization of p27Kip1. Biochem. J. 401, 247-256

Choedon, T., Mathan G., Arya, S., Kumar, V.L., Kumar, V. 2006. Anticancer and cytotoxic properties of the latex of Calotropis procera in a transgenic mouse model of hepatocellular carcinoma. World J. Gastroenterol. 12, 2517-2522

Kalra, N., Kumar, V. 2006. The X protein of hepatitis B virus binds to the F box protein Skp2 and inhibits the ubiquitination and proteasomal degradation of c-Myc. FEBS Lett. 580, 431-436

Recent Patents

Saxena, A.K., Gupta, B.D., Kapahi, B.K., Shanmugavel M., Mondhe, D.M., Qazi, G.N., Mathan, G., Kumar, V. 2006. A pharmaceutical composition useful for the treatment of hepatocellular carcinoma. PCT/IB2006/001355

Kumar, V.L., Kumar, V. 2005. Extraction of latex of Calotropis procera and to a method of preparation thereof. PCT/IN2005/000106