Ectopic expression of Bcl-2 switches over nuclear signalling for cAMP-induced apoptosis to granulocytic differentiation

The IPC-81 myeloid leukaemia cells undergo apoptosis rapidly after cAMP sti mulation (6 h) and cell death is prevented by early over-expression of the cAMP-inducible transcription repressor ICER, that blocks cAMP-dependent nuc lear signalling. Therefore, the expression of specific genes controlled by CRE-containing promoters is likely to determine cell fate. We now show that cAMP-induced cell death also is abrogated by the over-expression of the an ti-apoptotic gene, Bcl-2, Contrary to ICER, Bcl-2 does not affect cAMP-sign alling and allows the analysis of cAMP responses in death rescued cells. Th e Bcl-2 transfected cells treated with 8-CPT-cAMP were growth-arrested and thereafter cells embarked in granulocytic differentiation, with no addition al stimulation. Neutrophilic polynuclear granulocytes benefited from a long life span in GO-GI and remained functional (phagocytosis), This work demon strates that, using anti-apoptosis regulators, 'death signals' could be exp loited to trigger distinct biological responses. Indeed, cAMP signal can tr igger several simultaneously developing biological programs, in the same ce ll, i.e., growth regulation, apoptosis and differentiation. This cell syste m should prove useful to determine how a tumour cell can be re-programmed f or either apoptosis or functional maturation by physiological signals.