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Genetic inactivation of Par4 results in hyperactivation of NF‐κB and impairment of JNK and p38
Author(s) -
GarciaCao Isabel,
Lafuente María José,
Criado Luis M,
DiazMeco María Teresa,
Serrano Manuel,
Moscat Jorge
Publication year - 2003
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.1038/sj.embor.embor769
Subject(s) - p38 mitogen activated protein kinases , apoptosis , kinase , biology , hyperactivation , microbiology and biotechnology , tumor necrosis factor alpha , traf2 , regulator , signal transduction , protein kinase a , nf κb , cancer research , endocrinology , gene , genetics , tumor necrosis factor receptor
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‐κB 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‐α (TNF‐α) to induce apoptosis by increased activation of NF‐κB. Consistent with recent reports demonstrating the antagonistic actions of NF‐κB 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‐α 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.