Caspase-8-dependent HER-2 cleavage in response to tumor necrosis factor alpha stimulation is counteracted by nuclear factor kappaB through c-FLIP-L expression.
Cancer Res
; 64(8): 2684-91, 2004 Apr 15.
Article
en En
| MEDLINE
| ID: mdl-15087380
ABSTRACT
The oncoprotein HER-2/neu is a prosurvival factor, and its overexpression has been correlated with poor prognosis in patients with breast cancer. We report that HER-2 is a new substrate for caspase-8 and that tumor necrosis factor alpha (TNF-alpha) stimulation leads to an early caspase-8-dependent HER-2 cleavage in MCF7 A/Z breast adenocarcinoma cells defective for nuclear factor kappaB (NFkappaB) activation. We show that the antiapoptotic transcription factor NFkappaB counteracts this cleavage through induction of the caspase-8 inhibitor c-FLIP. Our results also demonstrate that this HER-2 cleavage contributes to the TNF-alpha-induced apoptosis pathway because ectopic expression of an uncleavable HER-2 protects NFkappaB-defective cells against TNF-alpha-mediated cell death. Therefore, we propose an original model in which NFkappaB exerts a new antiapoptotic function by counteracting TNF-alpha-triggered cleavage of the HER-2 survival factor.
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Banco de datos:
MEDLINE
Asunto principal:
Neoplasias de la Mama
/
Adenocarcinoma
/
Proteínas Portadoras
/
FN-kappa B
/
Factor de Necrosis Tumoral alfa
/
Receptor ErbB-2
/
Caspasas
/
Péptidos y Proteínas de Señalización Intracelular
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Cancer Res
Año:
2004
Tipo del documento:
Article
País de afiliación:
Bélgica