Nerve growth factor-dependent survival of CESS B cell line is mediated by increased expression and decreased degradation of MAPK phosphatase 1.
The sIgG(+) lymphoblastoid B cell line CESS spontaneously produces a high amount of nerve growth factor (NGF) and expresses both high affinity (p140(Trk-A)) and low affinity (p75(NTR)) NGF receptors. Autocrine production of NGF maintains the survival of CESS cells through the continuous deactivation of p38 MAPK, an enzyme able to induce Bcl-2 phosphorylation and subsequent cytochrome c release and caspase activation. In this paper, we show that NGF induces transcriptional activation and synthesis of MAPK phosphatase 1 (MKP-1), a dual specificity phosphatase that dephosphorylates p38 MAPK, thus preventing Bcl-2 phosphorylation. Furthermore, NGF increases MKP-1 protein stability by preventing its degradation through the proteasome pathway. Following NGF stimulation, MKP-1 protein mainly localizes on mitochondria, suggesting an interaction with p38 MAPK in this compartment. Incubation of CESS cells with MKP-1-specific antisense oligonucleotides induces cell death, which was not prevented by exogenous NGF. By contrast, overexpression of native MKP-1, but not of its catalytically impaired form, inhibits apoptosis induced by NGF neutralization in CESS cells. Thus, the molecular mechanisms underlying the survival function of NGF in CESS B cell line predominantly consist in maintaining elevated levels of MKP-1 protein, which controls p38 MAPK activation.
Rosini
Paolo
P
Department of Clinical Physiopathology, University of Florence, Viale Pieraccini 6, I-50139 Florence, Italy.
De Chiara
Giovanna
G
Bonini
Paolo
P
Lucibello
Maria
M
Marcocci
Maria Elena
ME
Garaci
Enrico
E
Cozzolino
Federico
F
Torcia
Maria
M
D017209:Apoptosis / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D018797:Cell Cycle Proteins; D002460:Cell Line; D002470:Cell Survival / Q000276:immunology; D003546:Cysteine Endopeptidases / Q000378:metabolism; D054638:Dual Specificity Phosphatase 1; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000201:enzymology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism; D020932:Nerve Growth Factor / Q000494:pharmacology*; D010749:Phosphoprotein Phosphatases; D010766:Phosphorylation / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
D018797:Cell Cycle Proteins; D017874:Immediate-Early Proteins; D009097:Multienzyme Complexes; D020932:Nerve Growth Factor; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; D017027:Protein Tyrosine Phosphatases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex