Inactivation of the inhibitory kappaB protein kinase/nuclear factor kappaB pathway by Par-4 expression potentiates tumor necrosis factor alpha-induced apoptosis.
J Biol Chem
; 274(28): 19606-12, 1999 Jul 09.
Article
de En
| MEDLINE
| ID: mdl-10391896
ABSTRACT
Par-4 is a novel protein identified in cells undergoing apoptosis. The ability of Par-4 to promote apoptotic cell death is dependent on the binding and inactivation of the atypical protein kinases C (PKCs). This subfamily of kinases has been reported to control nuclear factor kappaB (NF-kappaB) through the regulation of the IkappaB kinase activity. NF-kappaB activation by tumor necrosis factor alpha (TNFalpha) provides a survival signal that impairs the TNFalpha-induced apoptotic response. We show here that expression of Par-4 inhibits the TNFalpha-induced nuclear translocation of p65 as well as the kappaB-dependent promoter activity. Interestingly, Par-4 expression blocks inhibitory kappaB protein (IkappaB) kinase activity, which leads to the inhibition of IkappaB phosphorylation and degradation, in a manner that is dependent on its ability to inhibit lambda/iotaPKC. Of potential functional relevance, the expression of Par-4 allows TNFalpha to induce apoptosis in NIH-3T3 cells. In addition, the down-regulation of Par-4 levels by oncogenic Ras sensitizes cells to TNFalpha-induced NF-kappaB activation.
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Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Protéines de transport
/
Facteur de transcription NF-kappa B
/
Facteur de nécrose tumorale alpha
/
Apoptose
/
Protéines et peptides de signalisation intracellulaire
Type d'étude:
Prognostic_studies
Limites:
Animals
Langue:
En
Journal:
J Biol Chem
Année:
1999
Type de document:
Article
Pays d'affiliation:
Espagne