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First published online 23 May 2006
doi: 10.1242/jcs.02974

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Mechanisms for human cytomegalovirus-induced cytoplasmic p53 sequestration in endothelial cells

¹ Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA
² Department of Ophthalmology and Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA
³ Department of Developmental Neurobiology, The Burnham Institute, La Jolla, CA, USA
⁴ VRL Laboratories, San Antonio, TX, USA
⁵ Department of Medicine, University of Minnesota, Minneapolis, USA
⁶ Institute for Cancer Genetics, Columbia University, New York, USA

^* Author for correspondence (e-mail: xlwang{at}bcm.tmc.edu)

Accepted 8 March 2006

Human cytomegalovirus (HCMV) infection results in endothelial dysfunction, typically known as dysregulated apoptosis, and aberrant expression and sub-cellular localization of p53, a tumor suppressor that accumulates at the late stage of infection. In this study, we examined three hypotheses that could be responsible for HCMV-induced cytoplasmic p53 accumulation at the later stage of infection: hyperactive nuclear export, cytoplasmic p53 tethering and delayed p53 degradation. Leptomycin B treatment, a nuclear export inhibitor, was unable to reduce cytoplasmic p53, thereby eliminating the hyperactive nuclear export mechanism. The findings that nascent p53 still entered nuclei after the nuclear export inhibition indicated that cytoplasmic tethering may play a minor role. Cytoplasmic p53 was still observed after the translation activities were blocked by cycloheximide. There was more than an eight-fold increase in the cytoplasmic p53 half-life with abnormal p53 ubiquitination. Taken together, these results suggest that delayed degradation could be responsible for the cytoplasmic p53 accumulation. The general slow-down of the proteasomal activity and the dysregulated p53 ubiquitination process at the later stage of infection could contribute to the reduced cytoplasmic p53 degradation and might be relevant to dysregulated endothelial apoptosis. The HCMV-induced changes in p53 dynamics could contribute to endothelial dysfunction.

Key words: Human cytomegalovirus, p53, Endothelial dysfunction