Genetic inactivation of Par4 results in hyperactivation of NF-kappaB and impairment of JNK and p38.
EMBO Rep
; 4(3): 307-12, 2003 Mar.
Article
em En
| MEDLINE
| ID: mdl-12634851
ABSTRACT
The Par4 gene was first identified in prostate cells undergoing apoptosis after androgen withdrawal. PAR4 was subsequently shown to interact with, and inhibit, atypical protein kinase C isoforms, functioning as a negative regulator of the NF-kappaB pathway. This may explain its pro-apoptotic function in overexpression experiments. To determine the physiological role of PAR4, we have derived primary embryonic fibroblasts (EFs) from Par4(-/-) mice. We show here that loss of PAR4 leads to a reduction in the ability of tumour necrosis factor-alpha (TNF-alpha) to induce apoptosis by increased activation of NF-kappaB. Consistent with recent reports demonstrating the antagonistic actions of NF-kappaB and c-Jun amino-terminal kinase (JNK) signalling, we have found that Par4(-/-) cells show a reduced activation of the sustained phase of JNK and p38 stimulation by TNF-alpha and interleukin 1. Higher levels of an anti-apoptotic JNK-inhibitor protein, X-chromosome-linked inhibitor of apoptosis, in Par4(-/-) EFs might explain the inhibition of JNK activation in these cells.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
NF-kappa B
/
Receptores de Trombina
/
Proteínas Quinases Ativadas por Mitógeno
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
EMBO Rep
Ano de publicação:
2003
Tipo de documento:
Article