Title | Genetic inactivation of Par4 results in hyperactivation of NF-kappaB and impairment of JNK and p38. |
Publication Type | Journal Article |
Year of Publication | 2003 |
Authors | Garcia-Cao I, Lafuente MJosé, Criado LM, Diaz-Meco MTeresa, Serrano M, Moscat J |
Journal | EMBO Rep |
Volume | 4 |
Issue | 3 |
Pagination | 307-12 |
Date Published | 2003 Mar |
ISSN | 1469-221X |
Keywords | Animals, Apoptosis, Embryo, Mammalian, Fibroblasts, Gene Expression Regulation, Interleukin-1, JNK Mitogen-Activated Protein Kinases, MAP Kinase Signaling System, Mice, Mice, Knockout, Mitogen-Activated Protein Kinases, NF-kappa B, p38 Mitogen-Activated Protein Kinases, Receptors, Thrombin, Restriction Mapping, Tumor Necrosis Factor-alpha, X Chromosome |
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. |
DOI | 10.1038/sj.embor.embor769 |
Alternate Journal | EMBO Rep |
PubMed ID | 12634851 |
PubMed Central ID | PMC1315897 |
Related Faculty:
Jorge Moscat, Ph.D. Maria Diaz-Meco Conde, Ph.D.