The sIgG+ lymphoblastoid B cell line CESS spontaneously produces a high amount of nerve growth factor (NGF) and expresses both high affinity (p140Trk-A) and low affinity (p75NTR) 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. The lymphoblastoid CESS B cell line displays a CD19+, CD20-, CD44+, CD38+, CD77-, and IgGK+ surface phenotype, which suggests its origin from an antigen-selected, somatically hypermutated, and proliferating B lymphocyte, a stage ontogenetically close to that of memory B cells. Similar to memory B lymphocytes, CESS cells express both high affinity (p140Trk-A) and low affinity (p75NTR) NGF receptors, spontaneously produce high amounts of NGF, and utilize it for their own survival. In memory B lymphocytes and in the CESS B cell line, neutralization of endogenous NGF induces activation of p38 MAPK, its mitochondrial translocation, and phosphorylation of Bcl-2 protein.

NGF-dependent survival of CESS B cell line is mediated by increased expression and decreased degradation of MKP-1 / ROSINI P; DE CHIARA G; BONINI P; LUCIBELLO M; MARCOCCI ME; GARACI E; COZZOLINO F; M. TORCIA. - In: THE JOURNAL OF BIOLOGICAL CHEMISTRY. - ISSN 0021-9258. - STAMPA. - 279:(2004), pp. 14016-14023. [10.1074/jbc.M305356200]

NGF-dependent survival of CESS B cell line is mediated by increased expression and decreased degradation of MKP-1.

COZZOLINO, FEDERICO;TORCIA, MARIA
2004

Abstract

The sIgG+ lymphoblastoid B cell line CESS spontaneously produces a high amount of nerve growth factor (NGF) and expresses both high affinity (p140Trk-A) and low affinity (p75NTR) 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. The lymphoblastoid CESS B cell line displays a CD19+, CD20-, CD44+, CD38+, CD77-, and IgGK+ surface phenotype, which suggests its origin from an antigen-selected, somatically hypermutated, and proliferating B lymphocyte, a stage ontogenetically close to that of memory B cells. Similar to memory B lymphocytes, CESS cells express both high affinity (p140Trk-A) and low affinity (p75NTR) NGF receptors, spontaneously produce high amounts of NGF, and utilize it for their own survival. In memory B lymphocytes and in the CESS B cell line, neutralization of endogenous NGF induces activation of p38 MAPK, its mitochondrial translocation, and phosphorylation of Bcl-2 protein.
2004
279
14016
14023
ROSINI P; DE CHIARA G; BONINI P; LUCIBELLO M; MARCOCCI ME; GARACI E; COZZOLINO F; M. TORCIA
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/224460
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