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

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 cou...

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Published in:	Journal of cell science Vol. 119; no. 12; pp. 2457 - 2467
Main Authors:	Utama, B, Shen, Y.H, Mitchell, B.M, Makagiansar, I.T, Gan, Y, Muthuswamy, R, Duraisamy, S, Martin, D, Wang, X, Zhang, M.-X, Wang, J, Vercellotti, G.M, Gu, W, Li Wang, X
Format:	Journal Article
Language:	English
Published:	England The Company of Biologists Limited 15-06-2006
Subjects:	Apoptosis - drug effects Apoptosis - physiology Cell Nucleus - metabolism Cell Nucleus - virology Cells, Cultured Cycloheximide - pharmacology Cytomegalovirus - physiology Cytomegalovirus Infections - virology Cytoplasm - metabolism Cytoplasm - virology Endothelial Cells - metabolism Endothelial Cells - virology Exportin 1 Protein Human cytomegalovirus Humans Karyopherins - biosynthesis Proto-Oncogene Proteins c-mdm2 - drug effects Proto-Oncogene Proteins c-mdm2 - metabolism Receptors, Cytoplasmic and Nuclear - biosynthesis RNA, Messenger - metabolism Time Factors Tumor Suppressor Protein p53 - drug effects Tumor Suppressor Protein p53 - metabolism Ubiquitin - metabolism
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Summary:	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.
Bibliography:	http://jcs.biologists.org/ ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1
ISSN:	0021-9533 1477-9137
DOI:	10.1242/jcs.02974