Disruption of B-cell homeostatic control mediated by the BLV-Tax oncoprotein: association with the upregulation of Bcl-2 and signaling through NF-kappaB.
Transactivating proteins associated with complex onco-retroviruses including human T-cell leukemia virus-1 (HTLV-1) and bovine leukemia virus (BLV) mediate transformation using poorly understood mechanisms. To gain insight into the processes that govern tumor onset and progression, we have examined the impact of BLV-Tax expression on ovine B-cells, the targets of BLV in experimentally infected sheep, using B-cell clones that are dependent on CD154 and gammac-common cytokines. Tax was capable of mediating progression of B-cells from cytokine dependence to cytokine independence, indicating that the transactivator can over-ride signaling pathways typically controlled by cytokine receptor activation in B-cells. When examined in the presence of both CD154 and interleukin-4, Tax had a clear supportive role on B-cell growth, with an impact on B-cell proliferation, cell cycle phase distribution, and survival. Apoptotic B-cell death mediated by growth factor withdrawal, physical insult, and NF-kappaB inhibition was dramatically reduced in the presence of Tax. Furthermore, the expression of Tax was associated with higher Bcl-2 protein levels, providing rationale for the rescue signals mediated by the transactivator. Finally, Tax expression in B-cells led to a dramatic increase of nuclear RelB/p50 and p50/p50 NF-kappaB dimers, indicating that cellular signaling through NF-kappaB is a major contributory mechanism in the disruption of B-cell homeostasis. Although Tax is involved in aspects of pathogenesis that are unique to complex retroviruses, the viral strategies associated with this transactivating oncoprotein may have wide-ranging effects that are relevant to other B-cell malignancies.
Szynal
Maud
M
Laboratory of Experimental Hematology, Bordet Institute, 1000 Brussels, Belgium.
Cleuter
Yvette
Y
Beskorwayne
Terry
T
Bagnis
Claude
C
Van Lint
Carine
C
Kerkhofs
Pierre
P
Burny
Aisene
A
Martiat
Philippe
P
Griebel
Philip
P
Van den Broeke
Anne
A
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism* / Q000821:virology; D023201:CD40 Ligand / Q000494:pharmacology / Q000502:physiology; D002453:Cell Cycle / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D002478:Cells, Cultured; D002999:Clone Cells / Q000166:cytology / Q000378:metabolism / Q000821:virology; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology; D016356:Gene Products, tax / Q000235:genetics / Q000378:metabolism*; D018014:Gene Transfer Techniques; D015847:Interleukin-4 / Q000494:pharmacology / Q000502:physiology; D001909:Leukemia Virus, Bovine / Q000737:chemistry; D016328:NF-kappa B / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D012190:Retroviridae / Q000235:genetics; D012756:Sheep; D015398:Signal Transduction; D015854:Up-Regulation
D016207:Cytokines; D016356:Gene Products, tax; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D023201:CD40 Ligand; D015847:Interleukin-4