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 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.
Garcia-Cao
Isabel
I
Department of Immunology and Oncology, Centro Nacional de Biotecnología, Universidad Autonoma de Madrid, Canto Blanco, 28049 Madrid, Spain.
Lafuente
María José
MJ
Criado
Luis M
LM
Diaz-Meco
María Teresa
MT
Serrano
Manuel
M
Moscat
Jorge
J
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000502:physiology; D005786:Gene Expression Regulation; D007375:Interleukin-1 / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D020935:MAP Kinase Signaling System / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D018179:Receptors, Thrombin / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D015183:Restriction Mapping; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014960:X Chromosome; D048051:p38 Mitogen-Activated Protein Kinases
D007375:Interleukin-1; D016328:NF-kappa B; D018179:Receptors, Thrombin; D014409:Tumor Necrosis Factor-alpha; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C112908:protease-activated receptor 4