Survival and death of prelymphomatous B-cells from N-myc/bcl-2 double transgenic mice correlates with the regulation of intracellular Ca2+ fluxes.
Coexpression of the proto-oncogenes c-myc and bcl-2 under the control of the immunoglobulin enhancer E mu provokes the rapid development of primitive lymphoid tumors in transgenic mice. In the present study we show that the myc family members N-myc and L-myc also cooperate with bcl-2 in oncogenesis and can provoke the development of more mature pre-B, B and T cell type lymphomas. The analysis of prelymphomatous B-cells from single E mu N-myc and bcl-2-Ig transgenic animals and from young, tumor free, double transgenic E mu N-myc/bcl-2-Ig mice revealed that E mu directed expression of N-myc leads to very rapid apoptosis after explantation and culturing compared to B-cells from normal mice. As expected, B-cells from bcl-2-Ig transgenics were protected to a certain degree from apoptosis. Strikingly however, B-cells from E mu N-myc/bcl-2-Ig double transgenic animals were found to be almost completely resistant towards a number of different apoptotic stimuli. Furthermore, after treatment with H2O2, which can trigger apoptosis, B-cells from E mu N-myc animals reach levels of intracellular free Ca2+ concentrations that are comparable to B-cells from normal mice, whereas B-cells from bcl-2-Ig or E mu N-myc/bcl-2-Ig double transgenic mice show no increase in intracellular Ca2+ concentrations after stimulation with H2O2. These findings suggest that the prevention of apoptosis conferred by bcl-2 correlates with the inhibition of intracellular Ca2+ fluxes whereas induction of apoptosis mediated by N-myc requires normal Ca2+ levels. We hypothesize therefore that the regulation of intracellular Ca2+ concentrations represent one important parameter in the oncogenic cooperation between bcl-2 and N-myc.
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D005260:Female; D015870:Gene Expression; D016259:Genes, myc / Q000502:physiology*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007424:Intracellular Fluid / Q000378:metabolism; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011230:Precancerous Conditions / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2
D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D006861:Hydrogen Peroxide; D002118:Calcium