DOWNREGULATION OF P53 PROTEIN BY KSHV VIRF1

这个子项目是众多研究子项目之一

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Infected cells recognize viral replication as a DNA damage stress and elicit ataxia telangiectasia-mutated (ATM)/p53-mediated DNA damage response signal transduction pathway as part of the host surveillance mechanisms, which ultimately induces the irreversible cell cycle arrest and apoptosis. Virus has evolved a variety of mechanisms to counteract this host intracellular innate immunity. Kaposi's Sarcoma-Associated Herpesvirus (KSHV) viral interferon regulatory factor 1 (vIRF1) interacts with cellular p53 tumor suppressor through its central DNA binding domain and this interaction inhibits transcriptional activation of p53. Here, we further demonstrate that KSHV vIRF1 downregulates total p53 protein level by facilitating its proteasome-mediated degradation. Detailed biochemical study showed that vIRF1 interacted with cellular ATM kinase through its carboxyl terminal transactivation domain, and that this interaction blocked the activation of ATM kinase activity induced by DNA damage stress. As a consequence, vIRF1 expression greatly reduced the level of the serine 15 phosphorylation of p53, resulting the increase of p53 ubiquitination and nuclear export and thereby, the decrease of its protein stability.