E1(-)E4(+) adenoviral gene transfer vectors function as a "pro-life" signal to promote survival of primary human endothelial cells.
Although endothelial cells are quiescent and long-lived in vivo, when they are removed from blood vessels and cultured in vitro they die within days to weeks. In studies of the interaction of E1(-)E4(+) replication-deficient adenovirus (Ad) vectors and human endothelium, the cells remained quiescent and were viable for prolonged periods. Evaluation of these cultures showed that E1(-)E4(+) Ad vectors provide an "antiapoptotic" signal that, in association with an increase in the ratio of Bcl2 to Bax levels, induces the endothelial cells to enter a state of "suspended animation," remaining viable for at least 30 days, even in the absence of serum and growth factors. Although the mechanisms initiating these events are unclear, the antiapoptoic signal requires the presence of E4 genes in the vector genome, suggesting that one or more E4 open reading frames of subgroup C Ad initiate a "pro-life" program that modifies cultured endothelial cells to survive for prolonged periods.
Ramalingam
R
R
Division of Pulmonary and Critical Care Medicine, and Division of Hematology-Oncology, The New York Hospital-Cornell Medical Center, New York, NY, USA.
Rafii
S
S
Worgall
S
S
Brough
D E
DE
Crystal
R G
RG
D000256:Adenoviridae / Q000235:genetics*; D017498:Adenovirus E1 Proteins / Q000235:genetics; D017504:Adenovirus E4 Proteins / Q000235:genetics; D017209:Apoptosis; D002455:Cell Division; D002470:Cell Survival; D002478:Cells, Cultured; D003470:Culture Media; D004730:Endothelium, Vascular / Q000166:cytology* / Q000502:physiology*; D017353:Gene Deletion; D005822:Genetic Vectors; D005966:Glucuronidase / Q000096:biosynthesis / Q000235:genetics; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D014162:Transfection / Q000379:methods; D014471:Umbilical Veins; D051028:bcl-2-Associated X Protein
D017498:Adenovirus E1 Proteins; D017504:Adenovirus E4 Proteins; C494826:BAX protein, human; D003470:Culture Media; D006133:Growth Substances; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D005966:Glucuronidase