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1.
Immun Inflamm Dis ; 1(1): 26-36, 2013 Oct.
Article in English | MEDLINE | ID: mdl-25400915

ABSTRACT

Pre-BCR acts as a critical checkpoint in B cell development. However, its signalling cascade still remains indistinctly characterised in human. We investigated pre-BCR signalling pathway to examine its regulation in normal primary pre-B lymphocytes and pre-B cell lines. In cell lines, early signalling events occurring after pre-BCR stimulation include phosphorylation of Lyn, Blk and Syk together with ZAP70, Btk, Vav, PLC-γ2 and various adaptor proteins, such as BLNK, LAB, LAT and SLP-76. Further downstream, these molecules induced activation of the PI3K/AKT and MAP-kinase resulting in an augmentation of canonical NF-κB pathways and cFos/AP1 activation. PI3K and MAPK exerted opposing effects on the pre-BCR-induced activation of the canonical NF-κB and c-Fos/AP1 pathways. Immediate nuclear export of FoxO3A and delayed import of IRF4 were additional events observed after pre-BCR crosslinking in primary cells. Pre-BCR-induced down-regulation of Rag1, Rag2, E2A and Pax5 transcripts occurred in a PI3K-dependent manner. Finally we bring evidence that pre-BCR stimulation or co stimulation with CD19 enhances cell cycle signal.

2.
Oncogene ; 23(17): 3040-7, 2004 Apr 15.
Article in English | MEDLINE | ID: mdl-15048088

ABSTRACT

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.


Subject(s)
Apoptosis/immunology , B-Lymphocytes/immunology , Caspases/metabolism , DNA-Binding Proteins/genetics , Interleukin-7/pharmacology , Milk Proteins , Trans-Activators/genetics , Apoptosis/drug effects , B-Lymphocytes/cytology , B-Lymphocytes/drug effects , B-Lymphocytes/physiology , Caspase 3 , Cell Death/drug effects , Cell Line , Humans , Mitochondria/drug effects , Mitochondria/immunology , STAT5 Transcription Factor , Tumor Suppressor Proteins
3.
Eur J Immunol ; 33(5): 1372-81, 2003 May.
Article in English | MEDLINE | ID: mdl-12731064

ABSTRACT

We have previously shown that Fas-induced apoptosis is markedly enhanced by IL-7 in human pre-B but not pro-B cell lines. In addition, pre-B cell receptor (pre-BCR) ligation significantly potentiates the IL-7 effects on Fas-triggered pre-B cell death. We show herein that transforming growth factor (TGF)-beta 1 sharply reduces Fas-induced death rate of pre-B but not pro-B cells. TGF-beta 1 causes inhibition of Fas-mediated disruption of mitochondrial transmembrane potential and cleavage of caspase 8, Bid and caspase 3. Bcl2 expression is markedly increased in TGF-beta 1-treated pre-B cells, whereas cellular FLICE-like inhibitory protein long (c-FLIPL), Bcl-XL, Bax, and Bad expression remains unchanged. TGF-beta 1 causes a selective growth arrest of pre-B cells in G0/G1 phase of the cell cycle and induces a partial down-modulation of both Fas and pre-BCR expression. All TGF-beta 1-mediated effects, but Bcl2 up-regulation, can be reproduced by the LY294002 phosphatidylinositol 3-kinase (PI3K)/Akt inhibitor but not by inhibitors of the MAPK/ERK (MEK) and Janus kinase (Jak)/STAT pathways, which promote cell death. Akt phosphorylation is strongly inhibited by TGF-beta1 in pre-B but not pro-B cells and is not modified by Fas engagement. Altogether, our findings suggest that TGF-beta1 prevents Fas-induced apoptosis of pre-B lines by inhibiting PI3K pathway and by enhancing expression of Bcl2. They also suggest that the PI3K/Akt pathway is involved in the control of Fas and pre-BCR expression, a checkpoint in B cell development.


Subject(s)
Apoptosis/drug effects , B-Lymphocytes/physiology , Hematopoietic Stem Cells/physiology , Protein Serine-Threonine Kinases , Transforming Growth Factor beta/pharmacology , fas Receptor/physiology , B-Lymphocytes/drug effects , Cell Division/drug effects , Cell Line , Hematopoietic Stem Cells/drug effects , Humans , Mitochondria/physiology , Phosphoinositide-3 Kinase Inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , Proto-Oncogene Proteins c-akt , Proto-Oncogene Proteins c-bcl-2/analysis , Transforming Growth Factor beta1
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