Related Experiment Videos
Inhibition of p53 tumor suppressor by viral interferon regulatory factor
1Department of Microbiology and Molecular Genetics, Tumor Virology Division, New England Regional Primate Research Center, Harvard Medical School, Southborough, Massachusetts 01772, USA.
Abstract:
The irreversible cell cycle arrest and apoptosis induced by p53 are part of the host surveillance mechanisms for viral infection and tumor induction. Kaposi's sarcoma-associated herpesvirus (KSHV), the most recently discovered human tumor virus, is associated with the pathogenesis of Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. The K9 open reading frame of KSHV encodes a viral interferon (IFN) regulatory factor (vIRF) which functions as a repressor for cellular IFN-mediated signal transduction and as an oncoprotein to induce cell growth transformation. Here, we demonstrate that KSHV vIRF interacts with the cellular p53 tumor suppressor through the putative DNA binding region of vIRF and the central region of p53. This interaction suppresses the level of phosphorylation and acetylation of p53 and inhibits transcriptional activation of p53. As a consequence, vIRF efficiently prevents p53-mediated apoptosis. These results suggest that KSHV vIRF interacts with and inhibits the p53 tumor suppressor to circumvent host growth surveillance and to facilitate uncontrolled cell proliferation.
Insights
Kaposi's sarcoma-associated herpesvirus (KSHV) vIRF protein inhibits the p53 tumor suppressor. This interaction prevents p53-mediated apoptosis, promoting viral-driven cell proliferation and tumor development.
Area of Science:
- Oncology
- Virology
- Molecular Biology
Background:
- p53 is a crucial tumor suppressor involved in cell cycle arrest and apoptosis, acting as a defense against viral infections and tumor formation.
- Kaposi's sarcoma-associated herpesvirus (KSHV) is a human tumor virus linked to Kaposi's sarcoma and other diseases.
- KSHV encodes a viral interferon regulatory factor (vIRF) that acts as an oncoprotein, promoting cell growth.
Purpose of the Study:
- To investigate the interaction between KSHV vIRF and the p53 tumor suppressor.
- To elucidate the mechanism by which KSHV vIRF affects p53 function.
- To understand how KSHV evades host surveillance mechanisms.
Main Methods:
- Co-immunoprecipitation assays to demonstrate interaction between KSHV vIRF and p53.
- Western blotting to assess p53 phosphorylation and acetylation levels.
- Reporter assays to evaluate p53 transcriptional activity.
Main Results:
- KSHV vIRF directly interacts with the p53 tumor suppressor.
- This interaction leads to decreased phosphorylation and acetylation of p53.
- KSHV vIRF inhibits p53-mediated transcriptional activation and apoptosis.
Conclusions:
- KSHV vIRF antagonizes the p53 tumor suppressor pathway.
- Inhibition of p53 by KSHV vIRF facilitates viral-induced cell proliferation.
- This viral strategy circumvents host anti-tumor surveillance, contributing to KSHV pathogenesis.