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 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.
Séité
P
P
INSERM U496, Institut d'Hématologie, Hôpital St Louis, 75010-Paris, France.
Ruchaud
S
S
Hillion
J
J
Gendron
M C
MC
Bruland
O
O
Ségal-Bendirdjian
E
E
Doskeland
S O
SO
Lillehaug
J R
JR
Lanotte
M
M
D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle / Q000502:physiology; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism*; D000242:Cyclic AMP / Q000031:analogs & derivatives* / Q000494:pharmacology*; D053938:DNA Fragmentation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006098:Granulocytes / Q000166:cytology / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D013873:Thionucleotides / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D013873:Thionucleotides; C015929:8-((4-chlorophenyl)thio)cyclic-3',5'-AMP; D000242:Cyclic AMP