Genetic inactivation of Par4 results in hyperactivation of NF-kappaB and impairment of JNK and p38

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 functio...

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Bibliographic Details
Published in:EMBO reports 2003-03, Vol.4 (3), p.307-312
Main Authors: Garcia-Cao, Isabel, Lafuente, María José, Criado, Luis M, Diaz-Meco, María Teresa, Serrano, Manuel, Moscat, Jorge
Format: Article
Language:English
Subjects:
Animals
Apoptosis - drug effects
Embryo, Mammalian
Fibroblasts - physiology
Gene Expression Regulation
Interleukin-1 - pharmacology
JNK Mitogen-Activated Protein Kinases
MAP Kinase Signaling System - genetics
Mice
Mice, Knockout
Mitogen-Activated Protein Kinases - metabolism
NF-kappa B - metabolism
p38 Mitogen-Activated Protein Kinases
Receptors, Thrombin - deficiency
Receptors, Thrombin - genetics
Receptors, Thrombin - physiology
Restriction Mapping
Tumor Necrosis Factor-alpha - pharmacology
X Chromosome
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Summary: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.
ISSN:1469-221X