Interleukin-7 induces apoptosis of 697 pre-B cells expressing dominant-negative forms of STAT5: evidence for caspase-dependent and -independent mechanisms.
The transcription factors STAT5A and STAT5B (STAT: signal transducer and activator of transcription) play a major role in the signaling events elicited by a number of growth factor and cytokine receptors. In this work, we aimed to investigate the role of STAT5 in human precursor B cell survival by introducing dominant-negative (DN) forms of STAT5A or STAT5B in the 697 pre-B cell line. All clones expressing DN forms of either transcription factor exhibited a higher spontaneous apoptotic rate that was massively enhanced upon interleukin-7 (IL-7) stimulation. This was associated with caspase 8 cleavage, mitochondrial transmembrane potential disruption and caspase 3 activation. However, the DN forms of STAT5 did not alter the expression of Bcl-2, Bax, Bcl-x, Bim, A1 and Mcl1 proteins in IL-7-stimulated cells. The pancaspase inhibitor Z-Val-Ala-Asp-fluoromylmethyl ketone partially suppressed IL-7-mediated mitochondrial transmembrane potential disruption and cell death, suggesting that IL-7 induced the death of DN STAT5 expressing 697 cells through caspase-dependent and -independent mechanisms that both require mitochondrial activation.
Lanvin
Olivia
O
Laboratoire d'Immunologie, INSERM, EMI 0351, 3 rue des Louvels, 80036 Amiens, France.
Gouilleux
Fabrice
F
Mullié
Catherine
C
Mazière
Cécile
C
Fuentes
Vincent
V
Bissac
Eliane
E
Dantin
Françoise
F
Mazière
Jean-Claude
JC
Régnier
Aline
A
Lassoued
Kaiss
K
Gouilleux-Gruart
Valérie
V
D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics*; D006801:Humans; D015851:Interleukin-7 / Q000494:pharmacology*; D008894:Milk Proteins; D008928:Mitochondria / Q000187:drug effects / Q000276:immunology; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000235:genetics*; D025521:Tumor Suppressor Proteins
D004268:DNA-Binding Proteins; D015851:Interleukin-7; D008894:Milk Proteins; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; C494095:STAT5B protein, human; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases