Expression of the Bcl-2 homologue Mcl-1 correlates with survival of peripheral blood B lymphocytes.
Normal peripheral blood B lymphocytes undergo spontaneous apoptosis in vitro, and this process is regulated positively and negatively by several immunomodulatory stimuli. We have shown previously that Bcl-2 protein levels are unaltered by these factors, suggesting a Bcl-2-independent regulation of apoptosis in this system. Here, we have investigated the possibility that the three recently identified Bcl-2 homologues, Bax, Bcl-x, and Mcl-1, could be involved instead. Freshly isolated cells expressed both Bax and Mcl-1 protein, but only low levels of Bcl-xL and no detectable Bcl-xS, as determined by Western blot analysis. Upon culture of cells with apoptotic or survival stimuli, Bax and Bcl-xL protein levels remained relatively unchanged. By contrast, Mcl-1 levels decreased markedly in cells undergoing apoptosis in medium and, even more dramatically, after treatment with the apoptotic stimuli transforming growth factor beta 1 and forskolin. This decrease was rapid and preceded cell death. Furthermore, all the survival stimuli tested (interleukin 4, anti-IgM antibodies, and the phorbol ester 12-O-tetradecanoylphorbol-13-acetate) prevented the decline in Mcl-1 levels. This striking correlation between cell survival and Mcl-1 expression in peripheral blood B cells suggests the possible involvement of Mcl-1, instead of Bcl-2, in the regulation of apoptosis in these cells. The present study is the first one linking this novel Bcl-2 homologue to the control of cell death in normal cells.
Lømo
J
J
Department of Immunology, Norwegian Radium Hospital, Oslo, Norway.
Smeland
E B
EB
Krajewski
S
S
Reed
J C
JC
Blomhoff
H K
HK
D017209:Apoptosis / Q000502:physiology*; D001402:B-Lymphocytes / Q000502:physiology*; D015153:Blotting, Western; D002470:Cell Survival; D002478:Cells, Cultured; D006801:Humans; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
C494826:BAX protein, human; C494811:BCL2L1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein