The antiapoptotic role of Bcl-2 can be regulated by its phosphorylation in serine and threonine residues located in a nonstructured loop that links BH3 and BH4 domains. p38 MAPK has been identified as one of the kinases able to mediate such phosphorylation, through direct interaction with Bcl-2 protein in the mitochondrial compartment. In this study, we identify, by using mass spectrometry techniques and specific anti-phosphopeptide antibodies, Ser(87) and Thr(56) as the Bcl-2 residues phosphorylated by p38 MAPK and show that phosphorylation of these residues is always associated with a decrease in the antiapoptotic potential of Bcl-2 protein. Furthermore, we obtained evidence that p38 MAPK-induced Bcl-2 phosphorylation plays a key role in the early events following serum deprivation in embryonic fibroblasts. Both cytochrome c release and caspase activation triggered by p38 MAPK activation and Bcl-2 phosphorylation are absent in embryonic fibroblasts from p38 alpha knock-out mice (p38 alpha(-/-) MEF), whereas they occur within 12 h of serum withdrawal in p38 alpha(-/-) MEF; moreover, they can be prevented by p38 MAPK inhibitors and are not associated with the synthesis of the proapoptotic proteins Bax and Fas. Thus, Bcl-2 phosphorylation by activated p38 MAPK is a key event in the early induction of apoptosis under conditions of cellular stress.

De Chiara, G., Marcocci, M.e., Torcia, M., Lucibello, M., Rosini, P., Bonini, P., et al. (2006). Bcl-2 phosphorylation by p38 MAPK: Identification of target sites and biologic consequences. THE JOURNAL OF BIOLOGICAL CHEMISTRY, 281(30), 21353-21361 [10.1074/jbc.M511052200].

Bcl-2 phosphorylation by p38 MAPK: Identification of target sites and biologic consequences

GARACI, ENRICO;
2006-01-01

Abstract

The antiapoptotic role of Bcl-2 can be regulated by its phosphorylation in serine and threonine residues located in a nonstructured loop that links BH3 and BH4 domains. p38 MAPK has been identified as one of the kinases able to mediate such phosphorylation, through direct interaction with Bcl-2 protein in the mitochondrial compartment. In this study, we identify, by using mass spectrometry techniques and specific anti-phosphopeptide antibodies, Ser(87) and Thr(56) as the Bcl-2 residues phosphorylated by p38 MAPK and show that phosphorylation of these residues is always associated with a decrease in the antiapoptotic potential of Bcl-2 protein. Furthermore, we obtained evidence that p38 MAPK-induced Bcl-2 phosphorylation plays a key role in the early events following serum deprivation in embryonic fibroblasts. Both cytochrome c release and caspase activation triggered by p38 MAPK activation and Bcl-2 phosphorylation are absent in embryonic fibroblasts from p38 alpha knock-out mice (p38 alpha(-/-) MEF), whereas they occur within 12 h of serum withdrawal in p38 alpha(-/-) MEF; moreover, they can be prevented by p38 MAPK inhibitors and are not associated with the synthesis of the proapoptotic proteins Bax and Fas. Thus, Bcl-2 phosphorylation by activated p38 MAPK is a key event in the early induction of apoptosis under conditions of cellular stress.
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore MED/07 - Microbiologia e Microbiologia Clinica
English
Con Impact Factor ISI
ACTIVATED PROTEIN-KINASE; B-CELL LINE; INDUCED APOPTOSIS; CARDIAC MYOCYTES; C-JUN; POLYACRYLAMIDE-GELS; FAMILY PROTEINS; DNA-DAMAGE; DEATH; BCL-X(L)
De Chiara, G., Marcocci, M.e., Torcia, M., Lucibello, M., Rosini, P., Bonini, P., et al. (2006). Bcl-2 phosphorylation by p38 MAPK: Identification of target sites and biologic consequences. THE JOURNAL OF BIOLOGICAL CHEMISTRY, 281(30), 21353-21361 [10.1074/jbc.M511052200].
De Chiara, G; Marcocci, Me; Torcia, M; Lucibello, M; Rosini, P; Bonini, P; Higashimoto, Y; Damonte, G; Armirotti, A; Amodei, S; Palamara, At; Russo, T; Garaci, E; Cozzolino, F
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/40405
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