title: Mechanisms for human cytomegalovirus-induced cytoplasmic p53 sequestration in endothelial cells.
abstract: 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.
authors.affiliation: Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Budi
authors.initials: B
authors.lastname: Utama
authors.forename: Ying H
authors.initials: YH
authors.lastname: Shen
authors.forename: Bradley M
authors.initials: BM
authors.lastname: Mitchell
authors.forename: Irwan T
authors.initials: IT
authors.lastname: Makagiansar
authors.forename: Yehua
authors.initials: Y
authors.lastname: Gan
authors.forename: Raveendran
authors.initials: R
authors.lastname: Muthuswamy
authors.forename: Senthil
authors.initials: S
authors.lastname: Duraisamy
authors.forename: David
authors.initials: D
authors.lastname: Martin
authors.forename: Xinwen
authors.initials: X
authors.lastname: Wang
authors.forename: Ming-Xiang
authors.initials: MX
authors.lastname: Zhang
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Greg M
authors.initials: GM
authors.lastname: Vercellotti
authors.forename: Wei
authors.initials: W
authors.lastname: Gu
authors.forename: Xing Li
authors.initials: XL
authors.lastname: Wang
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism / Q000821:virology; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D003587:Cytomegalovirus / Q000502:physiology*; D003586:Cytomegalovirus Infections / Q000821:virology*; D003593:Cytoplasm / Q000378:metabolism* / Q000821:virology; D042783:Endothelial Cells / Q000378:metabolism* / Q000821:virology; D006801:Humans; D028884:Karyopherins / Q000096:biosynthesis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D000097606:Exportin 1 Protein
chemical_list: D003513:Cycloheximide; D028884:Karyopherins; D051736:Proto-Oncogene Proteins c-mdm2; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; D000097606:Exportin 1 Protein; C497206:MDM2 protein, human