¹INSERM U496, Institut d'Hématologie, Hôpital St Louis, 75010-Paris, France

²Institut Jacques Monod, Université de Paris VII, place de Jussieu, 75005-Paris, France

³Department of Molecular Biology, Bergen High Technology Centre (BHTC), University of Bergen, Bergen, Norway

⁴Department of Cell Biology and Anatomy, University of Bergen, Bergen, Norway

Correspondence to: M Lanotte, INSERM U-496, Institut d'Hématologie, Hôpital St-Louis, 1, avenue Claude Vellefaux, 75475 Paris, Cedex 10, France. Tel: 33 1 53 72 21 56; Fax: 33 1 42 40 95 57; E-mail: mlanotte@jupiter.chu-stlouis.fr

^aCurrent address: IBMIG, ESA6031, CNRS, 40, avenue du Recteur Pineau, 86022 Poitiers Cedex, France

^bCurrent address: Institute of Cell and Molecular Biology, University of Edinburgh, Scotland

Edited by J Savill

The IPC-81 myeloid leukaemia cells undergo apoptosis rapidly after cAMP stimulation (6 h) and cell death is prevented by early over-expression of the cAMP-inducible transcription repressor ICER, that blocks cAMP-dependent nuclear 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 anti-apoptotic gene, Bcl-2. Contrary to ICER, Bcl-2 does not affect cAMP-signalling and allows the analysis of cAMP responses in death rescued cells. The Bcl-2 transfected cells treated with 8-CPT-cAMP were growth-arrested and thereafter cells embarked in granulocytic differentiation, with no additional stimulation. Neutrophilic polynuclear granulocytes benefited from a long life span in G0-G1 and remained functional (phagocytosis). This work demonstrates that, using anti-apoptosis regulators, 'death signals' could be exploited to trigger distinct biological responses. Indeed, cAMP signal can trigger several simultaneously developing biological programs, in the same cell, i.e., growth regulation, apoptosis and differentiation. This cell system should prove useful to determine how a tumour cell can be re-programmed for either apoptosis or functional maturation by physiological signals. Cell Death and Differentiation (2000) 7, 1081-1089.

Bcl-2; apoptosis; cell differentiation; cAMP-signalling; tumour cells; myeloid leukaemia

cAMP, cyclic adenosine monophosphate; 8-CPT-cAMP, 8-chloro-phenyl-thio-cAMP; CRE, c-AMP responsive element; FACS, fluorescence-activated cell sorting; PKC, Protein kinase C; PKA, c-AMP-dependent protein kinase; RAR, retinoic acid receptor; RXR, retinoid-X-receptor; TUNEL, terminal deoxynucleotide transferase-mediated dUTP-biotin nick-end labelling