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Division of Cancer Biology, Sunnybrook Health Science Centre and Department of Medical Biophysics, University of Toronto, Toronto, Ontario M4N 3M5, Canada
Upon cytokine withdrawal, interleukin (IL) 6-dependent murine plasmacytoma/hybridoma (myeloma) cells die in a way characteristic of apoptosis. Although gene transfer-mediated elevation in Bcl-2 protein levels has been demonstrated to repress a number of apoptotic death programs, it has been reported that ectopic bcl-2 expression is unable to prolong the survival of IL-6-deprived myeloma cells. In view of the recent identification of Bax as a protein that antagonizes the anti-apoptotic function of Bcl-2, we sought to determine whether the inability of transfected bcl-2 to protect against myeloma cell apoptosis might simply be due to insufficient levels of Bcl-2 protein produced to counteract this inhibitor. We show here that high-level expression of an exogenous bcl-2 gene, introduced into IL-6-dependent B9 myeloma cells via retroviral or bovine papilloma virus-based vectors, is indeed able to suppress apoptotic death following cytokine deprivation, with the extent of protection provided correlating with the amount of Bcl-2 protein synthesized in relation to the amount of endogenous Bax protein present in the cells. Of note, however, we found that IL-6-mediated suppression of B9 apoptosis does not involve induction of endogenous bcl-2 expression but is associated instead with the up-regulation of cellular bcl-x mRNA and Bcl-xL protein. These results thus extend the apoptotic death mechanisms that are inhibitable by both bcl-2 and bcl-xL to include that operative in IL-6-dependent cells and suggest that apoptosis in other cell types using the gp130 subunit of the IL-6 receptor might also be bcl-2 regulable or bcl-xL dependent.
1 This work was supported in part by Grant 4510 from the National Cancer Institute of Canada and Grant MT-11749 from the Medical Research Council of Canada. M. M. K. S. was the recipient of a University of Toronto Open Scholarship. R. G. H. is a Career Scientist of the Ontario Cancer Treatment and Research Foundation.
2 To whom requests for reprints should be addressed, at Division of Cancer Biology, Reichmann Research Building, S218, Sunnybrook Health Science Centre, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada.
Received 2/27/95. Accepted 4/21/95.
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