EBV utilizes a unique activation pathway for the transformation of human B cells.
EBV growth-transforms primate B lymphocytes and directly causes mono/multiclonal B cell lymphomas in vulnerable hosts. In this report we demonstrate that the degree of B cell transformability is not quantitatively determined at the level of either the saturable, transformation-prerequisite virus receptors or of the actual viral cell entry process. Instead, post-receptor binding events [Na+/H+ exchange, Ca2+ flux, tyrosine phosphorylation of two proteins (55-60/130-140 kd)] were identified as critical determinants of transformability. The presence of competent virus in transformable cells was per se insufficient for transformation: blockade of Ca2+ fluxes (or the antiport) generates virus-loaded cells that express viral genes but remain untransformed. Delayed induction by ionomycin of appropriately sized Ca2+ fluxes ([Ca2+]i greater than 180 less than 400 nM) re-starts transformation processes in EGTA-blocked, virus-loaded cells, perhaps providing a model for the study of virus re-activation. Overall, EBV induces unique cellular activation events different from non-oncogenic lymphocyte mitogens/activators, and, given the oncogenic potential of transformed cells in susceptible hosts, we hypothesize that these events describe a novel oncogenic transformation pathway.
Dosch
H M
HM
Hospital for Sick Children, Research Institute, Toronto, Ontario, Canada.
Lam
P
P
Hui
M F
MF
Hibi
T
T
Cheung
R K
RK
D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D001483:Base Sequence; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002472:Cell Transformation, Viral / Q000235:genetics / Q000276:immunology; D004279:DNA, Viral / Q000235:genetics; D015870:Gene Expression; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000276:immunology; D006801:Humans; D066298:In Vitro Techniques; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011991:Receptors, Virus / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers
D002352:Carrier Proteins; D004279:DNA, Viral; D011991:Receptors, Virus; D017923:Sodium-Hydrogen Exchangers; D011505:Protein-Tyrosine Kinases; D002118:Calcium