Differential effects of BCL-2 on survival and proliferation of human B-lymphoma cells following gamma-irradiation.
Bcl-2 can inhibit apoptosis induced by a variety of stimuli, including radiation and its presence in tumour cells would be expected to indicate poor prognosis. Bcl-2-expressing tumours, however, are often low-grade and highly responsive to therapy. To investigate this apparent paradox, we analysed in vitro the responses of Burkitt lymphoma (BL) cells to gamma-irradiation in the presence and absence of Bcl-2. High-level expression of Bcl-2 was shown to promote BL cell survival following irradiation. However, a significant proportion of Bcl-2-rescued cells subsequently underwent apoptosis after an extended period in culture. In addition, in different BL lines, Bcl-2 was found either to promote or to inhibit long-term proliferative activity following gamma-irradiation. This differential regulation of proliferation correlated both with differential effects of Bcl-2 on the cell cycle and with differences in p53 status. Thus, by one week after irradiation, BL cells expressing only wild-type p53 (wt/wt) had arrested in G1, whereas those with a mutant allele (wt/mu) were arrested in all phases of the cell cycle. The proportion of Bcl-2-rescued cells that subsequently underwent apoptosis was reduced by ligation of CD40 at the time of irradiation in wt/wt BL cells, but not in wt/mu cells. CD40-ligation reduced both G1-arrest and apoptosis in parallel. These results indicate that, whilst Bcl-2 can delay apoptosis in BL cells following gamma-irradiation, the protein can also cause growth-arrest and thereby promote apoptosis. Long-term survival following Bcl-2-mediated rescue of gamma-irradiated cells may depend on p53 status and require additional death-repressing or growth-promoting signals.
Milner
A E
AE
Department of Immunology, University of Birmingham Medical School, Edgbaston, UK.
Grand
R J
RJ
Vaughan
A T
AT
Armitage
R J
RJ
Gregory
C D
CD
D019013:CD40 Antigens / Q000378:metabolism; D002455:Cell Division / Q000502:physiology / Q000528:radiation effects; D002470:Cell Survival / Q000502:physiology / Q000528:radiation effects; D005720:Gamma Rays; D006801:Humans; D016393:Lymphoma, B-Cell / Q000473:pathology*; D011485:Protein Binding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism / Q000502:physiology*; D014407:Tumor Cells, Cultured
D019013:CD40 Antigens; D019253:Proto-Oncogene Proteins c-bcl-2