title: Genetic inactivation of Par4 results in hyperactivation of NF-kappaB and impairment of JNK and p38.
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.
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología, Universidad Autonoma de Madrid, Canto Blanco, 28049 Madrid, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Garcia-Cao
authors.forename: María José
authors.initials: MJ
authors.lastname: Lafuente
authors.forename: Luis M
authors.initials: LM
authors.lastname: Criado
authors.forename: María Teresa
authors.initials: MT
authors.lastname: Diaz-Meco
authors.forename: Manuel
authors.initials: M
authors.lastname: Serrano
authors.forename: Jorge
authors.initials: J
authors.lastname: Moscat
mesh_terms: 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
chemical_list: 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