INDUCTION OF BAX-ALPHA PRECEDES APOPTOSIS IN A HUMAN B-LYMPHOMA CELL-LINE - POTENTIAL ROLE OF THE BCL-2 GENE FAMILY IN SURFACE IGM-MEDIATED APOPTOSIS

The members of the bcl-2 gene family are major regulators of programmed cell death, but their role in sig-triggered apoptosis remains unclear. Using sensitive and resistant variants of the human B cell line BL-41, we studied the expression of the bcl-2 gene family during surface IgM-mediated apoptosis. We found constitutive Bcl-2 and Bcl-x expression, which remained unaltered after sig cross-linking, in both resistant and sensitive cells. This and other experiments suggest that constitutive expression of Bcl-2 or Bcl-x alone is not sufficient to protect from activation-induced cell death in B cells. We therefore investigated Bax-alpha, the death-promoting splice variant of Bax, and found strong induction of both mRNA and protein upon sig stimulation in sensitive cells. However, resistant subclones showed only weak expression,which was not inducible by sig cross-linking. We provide evidence that up-regulation of Bax-alpha and the resulting imbalance of Bcl-2/Bax might be a major regulator of sig-mediated apoptosis. Additionally, we found strong constitutive expression of Bcl-x(s), the death promoting variant of Bcl-x, in sensitive cells, whereas resistant cells showed only weak Bcl-x(s) expression. Thus, we observed a much stronger expression of the death-promoting proteins Bax-alpha (inducible) and Bcl-x(s) (constitutive) in sensitive cells than in resistant cells. We therefore propose a potential role of the novel bcl-2 gene family members bcl-x and bax in surface IgM-triggered apoptosis.