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 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.
Utama
Budi
B
Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA.
Shen
Ying H
YH
Mitchell
Bradley M
BM
Makagiansar
Irwan T
IT
Gan
Yehua
Y
Muthuswamy
Raveendran
R
Duraisamy
Senthil
S
Martin
David
D
Wang
Xinwen
X
Zhang
Ming-Xiang
MX
Wang
Jing
J
Wang
Jian
J
Vercellotti
Greg M
GM
Gu
Wei
W
Wang
Xing Li
XL
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
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